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home:publications:marshall_neurotalk2011 [07.15.2011] – [Transcript] jrfoutinhome:publications:marshall_neurotalk2011 [07.15.2011] – [Transcript] jrfoutin
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 Now our next speaker is Trevor Marshall and he is currently in the United States, the Director of Autoimmunity Research in Thousand Oaks in California. Since he is an Australian, he also keeps one foot in the door in Australia and he is adjunct professor in the faculty of Health Sciences at Murdock University, and that is in Western Australia. And I think he just went from the South to the West.\\ Now our next speaker is Trevor Marshall and he is currently in the United States, the Director of Autoimmunity Research in Thousand Oaks in California. Since he is an Australian, he also keeps one foot in the door in Australia and he is adjunct professor in the faculty of Health Sciences at Murdock University, and that is in Western Australia. And I think he just went from the South to the West.\\
  
-TM: Right, but we are still in the antipathy, so to that is something. But most of my work now is based in California with the Autoimmunity Research Foundation. \\+**TM:** Right, but we are still in the antipathy, so to that is something. But most of my work now is based in California with the Autoimmunity Research Foundation. \\
  
 **00:51\\ **00:51\\
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 This is a Web page or images off a web page which was produced by the National Institutes of Health about three or four years ago when they kicked off the Human Microbiome Project. And the Goal of the Human Microbiome is to look for microbes in and around the human body by using the DNA sequencing technology which is available these days.\\ This is a Web page or images off a web page which was produced by the National Institutes of Health about three or four years ago when they kicked off the Human Microbiome Project. And the Goal of the Human Microbiome is to look for microbes in and around the human body by using the DNA sequencing technology which is available these days.\\
  
-So instead of trying to culture the microbes, and we know that only about 2-5% of microbes are capable of being cultured, the DNA of the microbes was going to be able to be used to identify just what commensal or a pathogen with Homo sapiens.\\+So instead of trying to culture the microbes, and we know that only about 2-5% of microbes are capable of being cultured, the DNA of the microbes was going to be able to be used to identify just what commensal or a pathogen with //Homo sapiens//.\\
  
-The data is starting to come in. What we have found is that in Homo sapiens, there is in fact, thousands of species that are living in and around the human body. Whereas we have thought for so long that the human body is a sterile compartment, it is not sterile. It is not even close to being sterile.\\+The data is starting to come in. What we have found is that in //Homo sapiens//, there is in fact, thousands of species that are living in and around the human body. Whereas we have thought for so long that the human body is a sterile compartment, it is not sterile. It is not even close to being sterile.\\
  
-I am going to show you some of the science in a short time. I'm going to go first right quick and show you what we have actually done, and then hopefully, that will make you a little more interested in the science and keep your attention later on.\\+I am going to show you some of the science in a short time. I am going to go first right quick and show you what we have actually done, and then hopefully, that will make you a little more interested in the science and keep your attention later on.\\
  
 **02:23\\ **02:23\\
-Uniquely in Homo sapiens**\\ +Uniquely in //Homo sapiens//**\\ 
-What we contributed was that we noticed back about a decade ago, that uniquely in Homo sapiens, not in the great apes, but uniquely in Homo sapiens, intraphagocytic pathogens can persist by weakening innate immunity—innate immunity, not adaptive immunity—by disabling the transcription of a single key nuclear receptor, the VDR, type 1 nuclear receptor.\\+What we contributed was that we noticed back about a decade ago, that uniquely in //Homo sapiens//, not in the great apes, but uniquely in //Homo sapiens//, intraphagocytic pathogens can persist by weakening innate immunity—innate immunity, not adaptive immunity—by disabling the transcription of a single key nuclear receptor, the VDR, type 1 nuclear receptor.\\
  
-Because in Homo sapiens, and only in Homo sapiens, one nuclear receptor, the VDR, expresses genes for TLR2, as well as the Cathelicidin and beta-Defensin anti-microbial peptides (actually Cathelicidin is a protein that is broken down into peptides through microbicidal action), and all of which are essential to intracellular innate immune defenses.\\+Because in //Homo sapiens//, and only in //Homo sapiens//, one nuclear receptor, the VDR, expresses genes for TLR2, as well as the Cathelicidin and beta-Defensin anti-microbial peptides (actually Cathelicidin is a protein that is broken down into peptides through microbicidal action), and all of which are essential to intracellular innate immune defenses.\\
  
-So if you are a microbe that wants to persist inside the nucleated cells of the human body, it makes sense that you have evolved to knock out that receptor [VDR]. And in fact, that is what we found has been happening.\\+**So if you are a microbe that wants to persist inside the nucleated cells of the human body, it makes sense that you have evolved to knock out that receptor [VDR]. And in fact, that is what we found has been happening.**\\
  
 Because we found a drug that was already approved that we could retarget by changing the dosing. We could retarget this to reactivate VDR gene expression, or certainly, expression of genes by the VDR.\\ Because we found a drug that was already approved that we could retarget by changing the dosing. We could retarget this to reactivate VDR gene expression, or certainly, expression of genes by the VDR.\\
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 Then, by 2008, we collected some more data, just a quick retrospective analysis of it. We presented at the International Congress on Autoimmunity in Portugal, in 2008, about 100 patients with various diagnoses that were being treated with this VDR agonist.\\ Then, by 2008, we collected some more data, just a quick retrospective analysis of it. We presented at the International Congress on Autoimmunity in Portugal, in 2008, about 100 patients with various diagnoses that were being treated with this VDR agonist.\\
  
-A whole range of chronic diseases were found to be responding extremely well. We have a very unusual way of presenting this data, because we have a very low rate of failure. In fact, the rate of failure is only about 3 or 4 per 100 on this chart.\\+A whole range of chronic diseases were found to be responding extremely well. We have a very unusual way of presenting this data, because **we have a very low rate of failure**. In fact, the rate of failure is only about 3 or 4 per 100 on this chart.\\
  
 So we have actually spelled out year-by-year how patients responded to therapy. Rheumatoid Arthritis and Hashimoto’s Thyroiditis, of course, are up at the top. Uveitis, Psoriasis, Multiple Sclerosis down here, Psoriatic Arthritis, Diabetes and then we just had a few patients, one patient in fact, with Myasthenia Gravis and Diabetes Insipidus diagnoses.\\ So we have actually spelled out year-by-year how patients responded to therapy. Rheumatoid Arthritis and Hashimoto’s Thyroiditis, of course, are up at the top. Uveitis, Psoriasis, Multiple Sclerosis down here, Psoriatic Arthritis, Diabetes and then we just had a few patients, one patient in fact, with Myasthenia Gravis and Diabetes Insipidus diagnoses.\\
  
-But by an average of 36 months into treatment, 81% of the cohort were reporting reduced disease and symptoms. Many of them have gone on beyond that point.\\+**But by an average of 36 months into treatment, 81% of the cohort were reporting reduced disease and symptoms. Many of them have gone on beyond that point.**\\
  
 **06:17\\ **06:17\\
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 Quite an amazing case history, but it is //not// just Multiple Sclerosis.\\ Quite an amazing case history, but it is //not// just Multiple Sclerosis.\\
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 **07:56\\ **07:56\\
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 **08:54**\\ **08:54**\\
-**Homo sapiens VDR Olmesartan in LBP (note orientation of tetrazole)**\\+**//Homo sapiens// VDR Olmesartan in LBP (note orientation of tetrazole)**\\
  
 We actually simulated the operation of the VDR in real time with the drug in the binding pocket.\\ We actually simulated the operation of the VDR in real time with the drug in the binding pocket.\\
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 But we were also able to do this using Rattus norvegicus, the rat VDR, because there was an x-ray model available for the rat VDR.\\ But we were also able to do this using Rattus norvegicus, the rat VDR, because there was an x-ray model available for the rat VDR.\\
  
-What we found was the drug does not work in a rat, which is why probably no one else would know that [olmesartan] could be retargeted.\\ +**What we found was the drug does not work in a rat, which is why probably no one else would know that [olmesartan] could be retargeted.**\\ 
  
 **09:54**\\  **09:54**\\ 
-**Video [comparison video split screen of Homo sapiens and Rattus norvegicus]**\\+**Video [comparison video split screen of //Homo sapiens// and //Rattus norvegicus//]**\\
 If you look at the tetrazole ring, here, there are two strong hydrogen bonds in the human. Whereas in the rat, the tetrazole is not hydrogen bonded. It does not create the forces necessary to activate the VDR receptor.\\ If you look at the tetrazole ring, here, there are two strong hydrogen bonds in the human. Whereas in the rat, the tetrazole is not hydrogen bonded. It does not create the forces necessary to activate the VDR receptor.\\
  
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 In fact, a rat or mouse has different immune defenses as well. This a press release that just came out the 22nd of May 2011: "Ulcer bacteria may contribute to development of Parkinson's..." where they were able to induce Parkinson’s in a mouse strain of middle age mice with a delay of about 3-5 months.\\ In fact, a rat or mouse has different immune defenses as well. This a press release that just came out the 22nd of May 2011: "Ulcer bacteria may contribute to development of Parkinson's..." where they were able to induce Parkinson’s in a mouse strain of middle age mice with a delay of about 3-5 months.\\
  
-But I want to caution that the immune system in a mouse is totally different, probably needed a totally different species [pathogen mix] [than] what is needed [to induce Parkinson’s] in Homo sapiens.\\ +**But I want to caution that the immune system in a mouse is totally different, probably needed a totally different species [pathogen mix] [than] what is needed [to induce Parkinson’s] in Homo sapiens.**\\ 
    
 **10:54**\\ **10:54**\\
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 The microbiome project you may have seen on the first slide has now estimated that about 90% of the cells in the human body are bacterial in nature. Now, admittedly, bacterial cells are very, very small so the volumetric analysis would not be 90%, but by numerical analysis, about 90%.\\ The microbiome project you may have seen on the first slide has now estimated that about 90% of the cells in the human body are bacterial in nature. Now, admittedly, bacterial cells are very, very small so the volumetric analysis would not be 90%, but by numerical analysis, about 90%.\\
  
-When the immune system is enabled to start killing the pathogens inside cells, then many of those cells will die by autophagy and apoptosis and that necessarily increases the inflammation.\\+**When the immune system is enabled to start killing the pathogens inside cells, then many of those cells will die by autophagy and apoptosis and that necessarily increases the inflammation.**\\
  
 So the inflammation, the level of inflammation, be it subclinical or clinical, that the individual was experiencing necessarily increases when you start killing off the microbes.\\ So the inflammation, the level of inflammation, be it subclinical or clinical, that the individual was experiencing necessarily increases when you start killing off the microbes.\\
  
-If too many cells die at once, then the patient can become very, very ill, so immunostimulative therapy has to balance the rate of healing against the amount of immunopathology that is going to be endured by the patient.\\+**If too many cells die at once, then the patient can become very, very ill, so immunostimulative therapy has to balance the rate of healing against the amount of immunopathology that is going to be endured by the patient.**\\
      
 There are many groups that have tied inflammation to neurodegenerative diseases. Fred Gage's group has worked down at the Salk Institute. [It] is the one that I have been following the most.\\ There are many groups that have tied inflammation to neurodegenerative diseases. Fred Gage's group has worked down at the Salk Institute. [It] is the one that I have been following the most.\\
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 What you probably can not see from the back is if you look at the GFR, the GFR started at 70, which is not really good, and it started at about 70 and by about three years it had dropped down to 40 and it has maintained stably at about 40 for the subsequent three or four years of therapy.\\ What you probably can not see from the back is if you look at the GFR, the GFR started at 70, which is not really good, and it started at about 70 and by about three years it had dropped down to 40 and it has maintained stably at about 40 for the subsequent three or four years of therapy.\\
    
-When you have a patient with a GFR of 40, you would normally be pressing the panic buttons, but when you are changing the paradigm of the therapy that you are using, the panic buttons change. It is a very difficult problem that we have to solve.\\+When you have a patient with a GFR of 40, you would normally be pressing the panic buttons, but **when you are changing the paradigm of the therapy that you are using, the panic buttons change.** It is a very difficult problem that we have to solve.\\ 
      
 **15:45**\\ **15:45**\\
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 **21:06**\\ **21:06**\\
-**Mycobacterium tuberculosis**\\+**//Mycobacterium tuberculosis//**\\
  
 Also, Mycobacterium tuberculosis; some very good work done here in China, in 2003, which showed that the VDR receptor was downregulated when a cell was infected with Mycobacterium tuberculosis.\\ Also, Mycobacterium tuberculosis; some very good work done here in China, in 2003, which showed that the VDR receptor was downregulated when a cell was infected with Mycobacterium tuberculosis.\\
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 But we are still accumulating from long-term recovery data in Multiple Sclerosis, Schizophrenia, OCD, Dementia, Multiple System Atrophy, Amyotrophic Lateral Sclerosis, but all in very low numbers at this point.\\ But we are still accumulating from long-term recovery data in Multiple Sclerosis, Schizophrenia, OCD, Dementia, Multiple System Atrophy, Amyotrophic Lateral Sclerosis, but all in very low numbers at this point.\\
  
-The other thought I want to leave you with which is the thought that the previous speaker had, which is, that by the time the brain becomes infected, many systemic pathways are also already active, and vice versa, by the time systemic disease becomes manifest, the brain is very often affected, with a few exceptions, like ALS, which I am obviously intrigued with.\\+The other thought I want to leave you with which is the thought that the previous speaker had, which is, that **by the time the brain becomes infected, many systemic pathways are also already active, and vice versa, by the time systemic disease becomes manifest, the brain is very often affected, with a few exceptions,** like ALS, which I am obviously intrigued with.\\
  
-As we move to the future, there really has to be a choice made, by the physician or by the patient, for immunosuppression to give short term productivity/long term relapse and immobility—and immunostimulation to give short term inability and the long term productivity.\\+As we move to the future, **there really has to be a choice made, by the physician or by the patient, for immunosuppression to give short term productivity/long term relapse and immobility—and immunostimulation to give short term inability and the long term productivity.**\\
  
 **25:29**\\ **25:29**\\
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 **Q1:** Well, thanks. There is something on my mind that I would like to start. What do we look for? Like you say, these bugs, we are looking within the cells so there is not so much external. Normal septic person apparently as I understand it. So what, how can we test for this purpose?\\ **Q1:** Well, thanks. There is something on my mind that I would like to start. What do we look for? Like you say, these bugs, we are looking within the cells so there is not so much external. Normal septic person apparently as I understand it. So what, how can we test for this purpose?\\
  
-**TM:** It is even more complex than that. That optical microscopy that I showed you, what we do there is we put blood between two cover slips and then allow the blood to age. Between about six and thirty-six hours the cells that are infected start to explode like that. So you look at them after thirty-six hours and there is just debris, there are no signs of cells. So in typical sampling operations that one does in a clinical basis, you do not see this.\\+**TM:** It is even more complex than that. That optical microscopy that I showed you, what we do there is we put blood between two cover slips and then allow the blood to age. Between about six and thirty-six hours the cells that are infected start to explode like that. So you look at them after thirty-six hours and there is just debris, there are no signs of cells. So **in typical sampling operations that one does in a clinical basis, you do not see this.**\\
    
 **Q1:** Yes, you have access to a regular microscope slide so you can look at brain tissue? When you are looking at a Parkinson's brain, you can not see anything.\\ **Q1:** Yes, you have access to a regular microscope slide so you can look at brain tissue? When you are looking at a Parkinson's brain, you can not see anything.\\
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 **TM:** Very quickly. The body changes. The hormonal balance changes very quickly within two to three weeks.  **TM:** Very quickly. The body changes. The hormonal balance changes very quickly within two to three weeks. 
 If people are on thyroid medication, that has to be continuously modified, because usually within 18 months they are off thyroid medications. The whole balance changes very quickly with the immunopathology setting in and with the therapy.\\ If people are on thyroid medication, that has to be continuously modified, because usually within 18 months they are off thyroid medications. The whole balance changes very quickly with the immunopathology setting in and with the therapy.\\
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