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+ | ===== Transcript ===== | ||
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+ | Okay, so this is going to be a very different presentation because I'm going to focus on Homo sapiens, and I'm going to focus on the diseases of homo sapiens because that is what interests me most of all. I'm going to talk about metagenomics. This is a field that in just the last three, four years has gone from nothing to an explosive growth of knowledge. The early work that we saw in the, well it wasn't early work but, the earliest work was done in the marine environment, | ||
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+ | So metagenomics got off to a very quick start with, with mice. And early work from Jeff Gordon' | ||
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+ | This slide was presented by Claire Fraser-Liggett, | ||
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+ | Now EMBL in Europe has, is just in the middle of a big study, and they' | ||
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+ | Now this is also from Claire Fraser-Liggett' | ||
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+ | You see the difficulty with the human microbiome is its sheer complexity. This is the salivary microbiome which was produced by the group at Max Plank, published in Genome Research back two years ago. And this was sampled at twelve places around the planet, and multiple individuals at each location. Once again they found that there was more statistical variation between individuals than there was from location to location. But once again there was no real statistical inference that could be drawn, except that there was a heck of a lot of species that were identified in the saliva of healthy individuals. Things such as Yersinia. It's printed in fine print because there' | ||
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+ | So you can try and examine what's going on under light microscopy. This is an infected cell, an infected monocyte actually from a patient with Chronic Fatigue Syndrome. They tend to be very ill and its very easy to pick up the infected cells. But with light microscopy, you're fairly limited with what you can see. There' | ||
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+ | Okay, so transmission electron microscopy – that's the next step – and this is a study from the Wirostko group at Columbia University back in the 1980' | ||
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+ | This particular concept of the computational microscope was presented by Klaus Shulten, University of Illinois at Urbana-Champagne. Klaus really, and his group, were one of the pioneers in mathematical computer analysis of biological processes. And Klaus says that his microscope is made of Chemistry, Physics, Mathematics, | ||
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+ | Now I haven' | ||
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+ | Now why is this important, why was this interesting to me? Well, in homo sapiens, and only in homo sapiens – even in the higher primates this is not the case – but in homo sapiens and only in homo sapiens – one nuclear receptor, the VDR, expresses genes for TLR2 as well as Cathelicidin and beta-Defensin anti-microbial peptides – or antimicrobials, | ||
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+ | If you look at human chronic diseases, then you'll find that the human body exhibits VDR dysfunction in at least the following diseases: depression, multiple sclerosis, arthritis, lupus, sarcoidosis, | ||
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+ | If we take typical pathogens that we know cause human chronic disease, or are associated with human chronic disease – EBV – it knocks down the VDR very heavily, especially in lymphoblastoid cell lines such as in the bone marrow, peripheral blood cells to a somewhat lesser degree. And estrogen receptor beta is knocked down very heavily as well. That's not surprising because estrogen receptor beta is responsible for the VDR precursor protein. Similarly for Mycobacterium tuberculosis, | ||
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+ | And what we've managed to do in the last 8 years is using that drug I showed you earlier to reactivate the VDR, we've been able to work with our clinical collaborators worldwide on a whole range of chronic inflammatory diseases and show the disease processes can actually be reversed. I'm not going to go into how much they can be reversed because the state of health is a moving target in and of itself. But certainly the patients can be returned to the work force, returned to their family, and be very very happy people. And what this graph shows in some great detail is by an average 36 months, range from 18 to 53 in our cohort, 81% of the cohort reported reduced disease and symptoms. This is an observational retrospective, | ||
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+ | Q: What is the mass of the microbiome in a typical human being? | ||
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+ | A: Well that too was discussed in Vancouver. And the original NIH estimate was 90% of human cells are likely bacterial cells. The current estimate is 99%. So even that is a moving target at this point as discovery continues forward. There' | ||
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+ | Q: How much of it gets into the blood, I mean do these peptides, proteins that you mentioned.... | ||
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+ | A: Nobody knows, but certainly, you saw it, the cell that was disintegrating, | ||
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+ | Q: What was the name of that drug again? | ||
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+ | A: Olmesartan. Olmesartan Medoxomil is the drug. It's a sartan, an angiotensin receptor blocker. Its primary target is the angiotensin nuclear receptor, but unique amongst all the small molecules that are currently available, it has a significant effect on a number of other receptors; the key one in this case being VDR. And at normal doses, well at reasonable doses 4 to 6 times higher than you'd use for hypertension, | ||
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+ | Q: Why is the human VDR so different from the other primates? | ||
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+ | A: Well it's because of the transcriptome. There' | ||
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+ | Q: This may be a question but, the other one that strikes me as being very important is... the microbiome is absolutely essential for our good health too, right? | ||
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+ | A: Do we know that for sure? | ||
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+ | Q: I mean I'm just saying presumably, if it's there ... | ||
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+ | Q: Well, let me give you one data point. When I gave the keynote at the World Gene Congress down at Foshan in 2008, I showed a slide which had Lactobacillus on it, so called “friendly bacteria.” It highly increases the expression of a gene called ACE, angiotensin converting enzyme, which is right at the heart of many inflammatory diseases. So okay, Lactobacillus may be beneficial, but it may, and is likely to also be not necessarily totally beneficial. Whenever you've got such a huge genome, as any of the bacterial genomes, huge – a thousand odd genes – but you know what I'm saying, a very large number of genes, the likelihood that they' | ||
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+ | Q: My actual question was... is there any hints as to what kind of antibiotics we could use to address this issue? | ||
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+ | A: The body does a really good job. I mean all we do is use the Olmesartan to let the body start figuring out what … | ||
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+ | Q: you said in your initial remarks, when the body doesn' | ||
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+ | Q: Well we have. I mean that cohort, this cohort did use antibiotics for at least part of the recovery process but eventually they just go back to the Olmesartan, to the activating drug. No the immune system is pretty good at figuring it all out. I mean these endogenous antimicrobials don't target everything equally, you know. So that's the answer I'd like to give. Yes, we use antibiotics, | ||
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