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+ | **Type:** Conference presentation\\ | ||
+ | **Presenter: | ||
+ | **Conference: | ||
+ | **Location: | ||
+ | **Date: | ||
+ | **Additional content:** [[http:// | ||
+ | |||
+ | ===== Transcript ===== | ||
+ | |||
+ | This presentation is available on the DVD "The Science — | ||
+ | Marshall Protocol" | ||
+ | Research Foundation]]. | ||
+ | A lower quality real-time streaming version may be found at [[http:// | ||
+ | |||
+ | |||
+ | I've put some citations and disclosures and things on there. We | ||
+ | have a number of applications current with the Food and Drug | ||
+ | Administration in the USA. | ||
+ | |||
+ | We've had [phase 3 testing designation] approvals for two | ||
+ | antibiotics, | ||
+ | talking with them about chronic fatigue syndrome and a number of | ||
+ | other studies that we're trying to get underway to move as quickly | ||
+ | as possible and consolidate on the Phase 2 studies that we | ||
+ | ourselves did. | ||
+ | |||
+ | And there' | ||
+ | and any of you can look up those numbers and look at it in more | ||
+ | detail at the science that I'm going to cover in the presentation. | ||
+ | 2 | ||
+ | |||
+ | I usually start with a quote from John Arbuthnot, 1692. John | ||
+ | Abiernot wrote the first book on statistics of the Laws of Chance | ||
+ | and of course it was about cards, playing cards, but it was the first | ||
+ | formal text on statistics. But he wrote this wonder passage that he | ||
+ | says: There are very few things which we know which are not | ||
+ | capable of being reduced to a mathematical reasoning. And | ||
+ | where a mathematical reasoning can be had, it's as great a folly to | ||
+ | make use of any other, as to grope for a thing in the dark when | ||
+ | you have a candle standing by you. | ||
+ | |||
+ | The primary difference between mathematical science and | ||
+ | evidence-based medicine is that one is definitive and one is | ||
+ | interpretive. Mathematical science, biomedical science tries to | ||
+ | define relationships between entities. And evidence-based | ||
+ | medicine tries to place reliable interpretations on observational | ||
+ | data. Primarily, I mean, there' | ||
+ | True science, the primary difference between them is that true | ||
+ | science has really no concept of weight of evidence, that the | ||
+ | hypothesis is advanced. E equals MC squared, for example, it's | ||
+ | tested and it stands until it's improved or rejected. And if the | ||
+ | problem is deterministic, | ||
+ | |||
+ | Now of course in medicine most of the problems are not | ||
+ | deterministic — yet, but as our knowledge advances more and | ||
+ | more of the medical mysteries, if you like, clinical mysteries, start | ||
+ | to succumb to molecular biology and that's what I'm going to talk | ||
+ | about today. | ||
+ | |||
+ | It's very important that both the molecular biology and the | ||
+ | clinical sides of medicine work together in close concert. And this | ||
+ | is the example that I'm going to discuss. It's from the Lancet. Dr. | ||
+ | D.S. Grimes wrote a hypothesis in July of this year [2006] which | ||
+ | was titled: "Are Statins Analogues of Vitamin D?" And Dr. Grimes | ||
+ | had derived his hypothesis from the following observations: | ||
+ | Vitamin D is good for you, statins are good for you, therefore, | ||
+ | statins must be similiar to Vitamin D. Now I'm being very harsh | ||
+ | there and it's a much better hypothesis than that. You need to look | ||
+ | in detail at it, but that's the essence that I pulled out of it. | ||
+ | |||
+ | The problem that Dr. Grimes has in analyzing this particular | ||
+ | question using evidence-based medicine is that there are far too | ||
+ | many degrees of freedom. You have the degrees of freedom | ||
+ | related as to how the statins act — and clinical medicine has no | ||
+ | idea how the statins act, how Vitamin D acts — and clinical | ||
+ | medicine has very little idea of how Vitamin D acts. And then of | ||
+ | course you've got the experimental degrees of freedom as well that | ||
+ | are going to come into the data and make it very difficult to draw | ||
+ | a good conclusion. And of course Dr. Grimes really wasn't able to | ||
+ | do so. | ||
+ | |||
+ | However, my letter was published which did solve the dilemma | ||
+ | because, by recourse, the molecular biology, I do know what the | ||
+ | statins do and I've also got a pretty good idea what the Vitamine D | ||
+ | does. And because I can reduce that to mathematics with the | ||
+ | molecular biology it's very easily communicable to people that can | ||
+ | understand molecular biology. And later in the presentation I'll go | ||
+ | over the statins. | ||
+ | 3 | ||
+ | So clearly that's a gap in evidence-based medicine, but you | ||
+ | know the biochemists are also failing because a search at PubMed | ||
+ | shows an average of one paper a day is currently being published | ||
+ | about the VDR, the Vitamin D receptor. And if Dr. Grimes had | ||
+ | been following this literature it would have helped him alot in | ||
+ | understanding at least half of his conceptual problems. | ||
+ | |||
+ | Yet, the insight resulting from the knowledge about the nuclear | ||
+ | receptor, the VDR, are not being communicated through to the | ||
+ | physicians who are on the front lines. | ||
+ | |||
+ | One-paper-a-day, | ||
+ | Somebody the other day wrote that I am alone in saying that | ||
+ | Vitamin D is a steroid. Well, I'm sorry. You cannot read these one- | ||
+ | paper-a-day on the VDR and the nuclear receptors in PubMed | ||
+ | without understanding that everybody that's working in this field | ||
+ | has come to that same conclusion. | ||
+ | |||
+ | But the biochemists, | ||
+ | that information across to the clinicians. It's very important that | ||
+ | both phases of medicine work in concert. And one objective of this | ||
+ | presentation is to share what we now know about the Vitamins D | ||
+ | and how they affect both the immune system and the endocrine | ||
+ | homeostasis. | ||
+ | |||
+ | Th1 inflammatory disease is defined as disease which results | ||
+ | from a significant increase in the expression activity of interferon | ||
+ | gamma. It's a paracine cytokine, very hard to measure and it | ||
+ | doesn' | ||
+ | to look at other cytokines and try to draw an inference about what | ||
+ | interferon gamma probably is. | ||
+ | |||
+ | Well, unfortunately that doesn' | ||
+ | considerable confusion in trying to determine whether patients are | ||
+ | exhibiting inflammation of type Th1 or Th2. Th1 being innate | ||
+ | immunity. Th2 being adaptive immunity, broadly speaking. | ||
+ | Now in 2001, we noted that interferon gamma catalyzed by a | ||
+ | large amount thirty times, up to thirty times the formation of a | ||
+ | secosteroid which did circulate as a hormone: 1,25 | ||
+ | dihydroxyvitamin D. And we've used that marker in our ongoing | ||
+ | research. | ||
+ | |||
+ | Most diagnoses are normally thought to come from an | ||
+ | autoimmune pathogenesis or of type Th1. These range from | ||
+ | anorexia nervosa through diabetes and rheumatoid arthritis to | ||
+ | sarcoidosis, | ||
+ | conditions with our antibacterial protocol in the Phase 2 trials have | ||
+ | also observed that the following neurologic manifestations resolve | ||
+ | as the patient recovers: The inflammation disappears, excessive | ||
+ | aggression starts to disappear, mild paranoia, mild obsession, and | ||
+ | compulsion — we actually have classic obsession compulsion | ||
+ | disorder amongst our cohort, loss of memory, loss of cognitive | ||
+ | ability, and attention disorders, bipolar disorders, and even | ||
+ | suicidal ideation. | ||
+ | |||
+ | |||
+ | So over the last five years from early 2002, we have conducted | ||
+ | an observational, | ||
+ | antibacterial therapy in a variety of Th1 diagnoses. I've given a | ||
+ | quote there from the FDA Deputy Commissioner for Medical and | ||
+ | Scientific Affairs. It's a good quote and the paper, the complete | ||
+ | paper at the bottom I recommend to any of you who are involved | ||
+ | in clinical study design. This represents a major change in the | ||
+ | thinking of the regulators about how trials should be designed. | ||
+ | They should be designed to be successful and actually produce | ||
+ | results is what the FDA is starting to say now. I'll just refer you to | ||
+ | his paper and move onto our next slide. | ||
+ | |||
+ | One of the first big breakthroughs we came across was to | ||
+ | understand that antibodies themselves were not capable of making | ||
+ | the patients as sick as they were presenting. | ||
+ | |||
+ | Now Pasteur said that "in science chance favors the prepared | ||
+ | mind." So there' | ||
+ | — chance, and when it's in front of you, you can see it and | ||
+ | understand what it is, that's the prepared mind. And you need | ||
+ | both those elements to make discoveries. And we were lucky. We | ||
+ | noted, we had started with the disease sarcoidosis which is really | ||
+ | an end-stage Th1 disease similar to MS and ALS. It kills pretty | ||
+ | quickly after diagnosis. And we noted that the number of | ||
+ | sarcoidosis patients had case histories involving phases where | ||
+ | antibodies had been clinically recorded, but where the antibodies | ||
+ | have disappeared as the disease progressed to sarcoidosis. | ||
+ | |||
+ | So I've shown time one here health and time ' | ||
+ | at lupus SLE and rheumatoid arthritis diagnoses, both of which | ||
+ | involve specific antibody presentations in order for the diagnosis to | ||
+ | have been made, and the patients later progressed from those | ||
+ | diseases to the end-state of sarcoidosis. | ||
+ | |||
+ | The interesting thing was that sarcoidosis there are usually no | ||
+ | antibodies. There is usually a very low sedimentation rate | ||
+ | indicating that there' | ||
+ | system is not feeling anything. And that's one of the reasons it's | ||
+ | such an idiopathic and has been such a puzzling disease. | ||
+ | Yet, when you look at the malaise suffered by the patients, the | ||
+ | malaise is a straight line. There is no peaking of the malaise that | ||
+ | was coincident with the peaking of the antibodies. In fact, the | ||
+ | antibodies just seem to be bystanders, if you like, of the main | ||
+ | disease process. When we understood that, that was about in late | ||
+ | 2003 – early 2004, we opened up the Phase 2 study to allow | ||
+ | different inflammatory diagnoses to become part of the study. And | ||
+ | in particular that was when we started taking in the chronic fatigue | ||
+ | syndrome patients, the lyme disease, chronic lyme disease | ||
+ | patients, the rheumatoid arthritis, Hashomoto thyroiditis, | ||
+ | rest of them. | ||
+ | |||
+ | And this is what we found. In 2004, we published our initial | ||
+ | results which were basically just of the sarcoidosis subset of the cohort in Autoimmunity Reviews. But I travelled to Karolinska | ||
+ | Institute in Stockholm in May [2006] and I gave the following | ||
+ | figures for the recovery rate of key autoimmune diagnoses which | ||
+ | were extracted from our Phase 2/3 reports as of May 2006. | ||
+ | Now these are people who have been on the protocol typically | ||
+ | eighteen months and are well advanced on their road to recovery, | ||
+ | and I have two numbers here, for example rheumatoid arthritis, we | ||
+ | have the total number in the cohort, that have been in the cohort | ||
+ | eighteen months which is relatively low at that point, eight. And | ||
+ | then the number that we're reporting recovery in this case it's very | ||
+ | high. It is very high in this disease which is seven. Hashimoto is | ||
+ | twenty out of twenty-five. Osteoarthritis we're at a five. CFS, we've | ||
+ | been enrolling for quite a long time so we have a large number in | ||
+ | the cohort. And forty out of seventy-seven were reporting recovery | ||
+ | there after eighteen months. Cardiac arrythmia. Sarcoidosis has | ||
+ | the largest numbers of all because that's how we started the study | ||
+ | rolling. The diabetes, three out of five. Uveitis, twelve out of | ||
+ | eighteen. Fibromyglia syndrome twenty out of thirty-four. And | ||
+ | irritable bowel syndrome, eight out of ten. And that's just the | ||
+ | subset of the major diagnoses of the subjects in the cohort. | ||
+ | So how complex a Therapy is needed to address alll these | ||
+ | different Th1 Diagnoses? | ||
+ | |||
+ | So how complex a therapy was needed to address all of these | ||
+ | different Th1 diagnoses and induce a response from these | ||
+ | disparate, apparently disparate, groups of patients? | ||
+ | * Step one was to remove all sources of exogenous Vitamin D. | ||
+ | * Step two was to activate the VDR nuclear receptor with | ||
+ | Olmesartan. Olmesartan is a relatively new sartin drug. It's a very | ||
+ | active ligand, very polar ligand, and it targets a number of | ||
+ | receptors. And I'll talk more about that as we move on. | ||
+ | * Now for the first three months we administer a tetracycline, | ||
+ | preferably demeclocycline or minocycline every 48 hours starting | ||
+ | at an extremely low dose of 25mg every 48 hours working up to a | ||
+ | 100mg over the three months, typically. | ||
+ | * Then for the next nine months we add a second antibiotic, either | ||
+ | a low dose of azithromycin or clindamycin, | ||
+ | can handle. And the patients at this stage of the therapy after the | ||
+ | first three months have great deal of difficulty tolerating one-eighth | ||
+ | of the tablet of azithromycin every ten days added to the antibiotic | ||
+ | cocktail that they' | ||
+ | taking out the exogenuous Vitamin D and activating the innate | ||
+ | immunity via VDR, the sensitivity of the antibiotics is increased | ||
+ | many, many times over. | ||
+ | * And thereafter until complete recovery we administer pulsed, low | ||
+ | dose, three-antibiotic combo: minocycline, | ||
+ | clindamycin. | ||
+ | |||
+ | And this is the warning which I was told to put in by my FDA | ||
+ | liaison guy: Any one of the above steps may cause cell | ||
+ | apoptosis with an intensity requiring emergency room | ||
+ | care. Immunopathology must be respected. | ||
+ | Immunopathology is the lastest keyword for the damage done | ||
+ | to the body by the immune system doing its job. | ||
+ | 6 | ||
+ | So the immune system kills the bacteria and in this case you'll | ||
+ | see the bacteria intracellular. You lose cells, the cells die when the | ||
+ | bacteria are killed inside them. The cytokine storm and just | ||
+ | cleaning out the dead cells profoundly affects the malaise and | ||
+ | general health of the patient. So steps are needed to reduce | ||
+ | systemic damage as the intraphacytic pathogens are killed by the | ||
+ | innate immune system. And I've got the steps there and you can | ||
+ | look them up from the PDF on the web. | ||
+ | |||
+ | The key thing is that the rate of bacterial death is controlled by | ||
+ | inhibiting protein synthesis in the pathogens using intermittent low | ||
+ | doses of bacteriostatic antibiotics. And particularly bacteriostatic | ||
+ | antibiotics that target the translation of mRNA into proteins, target | ||
+ | the ribosome, the 70S bacterial ribosome. One bacterium is | ||
+ | weakened it's just one abx molecule is bound into one bacterial | ||
+ | ribosome. Low doses proportinately control the rates of bacterial | ||
+ | death. | ||
+ | |||
+ | So why? Why does this intervention appear to work when | ||
+ | previous antibiotic therapies didn't induce recovery? | ||
+ | |||
+ | The intervention works because, one, it's based on knowledge | ||
+ | derived from a rigorous theoretical model which is based on | ||
+ | molecular genomics. | ||
+ | |||
+ | The intervention recognizes that autoimmune disease is caused | ||
+ | by a defect in innate immunity and not by antibodies themselves. | ||
+ | It works because it recognizes that the VDR, long thought to be | ||
+ | just associated with Vitamin D, is actually at the heart of innate | ||
+ | immunity. | ||
+ | |||
+ | And it works because sequencing the genomes of the bacteria | ||
+ | and viruses has led us to an understanding of how these species | ||
+ | interact in a chronic environment — how they interact building up | ||
+ | slowly in a person' | ||
+ | the horizontal transfer of DNA occurs between the species, blurring | ||
+ | the distinction between species and allowing one species to | ||
+ | acquire the ability to invade the immune system from another | ||
+ | species. | ||
+ | |||
+ | And finally we recognize that the neonatal pathogens can | ||
+ | persist in the brain. | ||
+ | 7 | ||
+ | So let's go through those points one at a time. I just got a | ||
+ | picture there of one way of visualizing a large protein. In this case | ||
+ | a G-Protein coupled receptor GPCR. And we've got different | ||
+ | atoms there with force field radiuses and they were pretty colors | ||
+ | and they look nice and stuff but it's really hard to analyze much | ||
+ | from an image like this. | ||
+ | |||
+ | |||
+ | So biochemists tend to prefer to draw the large proteins in terms | ||
+ | of helical structures, loops, and the other structures that are | ||
+ | associated with the larger proteins, and the folds are visible. There | ||
+ | is more detail in that on the PDF. | ||
+ | |||
+ | When you want to look at interatomic reactions to try and figure | ||
+ | out whether you've got agonists or antagonists, | ||
+ | sit down a little bit more carefully and these 2-D plots, I prefer you | ||
+ | use the program called Ligplot, L-i-g-p-l-o-t, | ||
+ | type of diagram. Makes it extremely easy to see how any of the | ||
+ | amino residues such as this one exactly interacts with the ligand. | ||
+ | Each particular force is a significant, | ||
+ | is plotted on a graph like this. | ||
+ | 8 | ||
+ | So what can you do with all this technology? | ||
+ | |||
+ | This is a protein, SAR0276 which was taken from the genome | ||
+ | of a staph bug called MRSA252. And as you know MRSA252 is | ||
+ | one of the super bugs. This is a particularly nasty beast indeed. | ||
+ | But its genome is being fully sequenced by the Sanger Institute and | ||
+ | is one of the 363 fully sequenced bacterial pathogens that's now | ||
+ | available in the gene bank. | ||
+ | |||
+ | And when you go to the DNA and start looking for proteins | ||
+ | within that genome which are likely to have some pathogenic | ||
+ | intent, this is the first one that I came up with. I went looking for a | ||
+ | GPCR that was similar to CCR2B and CCR4, CXCR4. For | ||
+ | example, CXCR4 is where HIV enters the phagocytes through those | ||
+ | receptors. And I was looking for some way that these organisms | ||
+ | facilitate egress and ingress to and from the phagocytes. | ||
+ | |||
+ | Here is what I found, but what's particularly interesting is that | ||
+ | I've got this Olmesartan, this little ligand, the angiotensin receptor | ||
+ | blocker in here, and it binds very, very firmly into an active or an | ||
+ | inactiving position in that GPCR. It's a very highly polar ligand | ||
+ | and bascially any GPCR you find in a body, these new sartans and | ||
+ | statins will have some affinity for. Olmesartan happens to have a | ||
+ | high affinity for this particular bacterial protein, GPCR. | ||
+ | |||
+ | But you know what really surprised us was that the ARBs and | ||
+ | statins also had a very high affinity for the nuclear receptors, | ||
+ | particularly for VDR, PPAR gamma, and the other nuclear receptors | ||
+ | which are key to the immune system. So we were surprised | ||
+ | because while it was reasonable that these very active ligands | ||
+ | would bind into transmembrane receptors — the GPCR is a | ||
+ | transmembrane receptors — for them to bind into nuclear | ||
+ | receptors and into the ligand binding pocket in agonistic and | ||
+ | antagonistic locations was total surprise. | ||
+ | |||
+ | The nuclear receptive family I have on this slide I'm sure most of | ||
+ | you would be familiar with what we have there: The type 1 nuclear | ||
+ | receptors are the VDR — the Vitamin D receptor, the PPAR alpha | ||
+ | receptor, the gamma, the glucocorticoid receptor — that's the | ||
+ | home for cortisol, mineralcorticoid recceptor, progesterone | ||
+ | receptor, androgen receptor, estrogen receptor, thyroid alpha-1, | ||
+ | thyroid beta-1. | ||
+ | |||
+ | Now we have good x-ray structures of all of these nuclear | ||
+ | receptors so they' | ||
+ | these nuclear receptors because we know what the nuclear | ||
+ | receptors look like, very precisely. | ||
+ | 9 | ||
+ | So when we look at the Vitamin D Receptor, at this point each | ||
+ | one of those one-paper-a-day that's coming out on the VDR is | ||
+ | increasing our knowledge on what the VDR does. | ||
+ | But the key things that I want to point out at this point is that VDR is | ||
+ | the key to innate immunity. It's responsible for the expression of | ||
+ | toll-like receptor 2, toll-like receptor 4, the cathelicidin anti- | ||
+ | microbial peptides and the beta-Defensins. | ||
+ | |||
+ | The beta-Defensins are key to the way that the gut, the immune | ||
+ | system in the gut, handles flora and handles pathogens which | ||
+ | appear in the gut. Beta-Defensins and alpha-Defensins are very | ||
+ | active there. | ||
+ | |||
+ | The cathelicidin anti-microbial peptides typically tend to be | ||
+ | more active within the phagocytes themselves. | ||
+ | TLR4 is the receptor that is sensitive to lipopolysaccharide, | ||
+ | prototypical bacterial marker. TLR4 is sensitive to | ||
+ | lipopolysaccharides. TLR2 is sensitive to other bacterial lipo | ||
+ | proteins. | ||
+ | |||
+ | So if you're not expressing the TLR2, TLR4, and the antimicrobial | ||
+ | peptides very well, then the immune system, and particularly the | ||
+ | innate immune system, is not going to be functioning very well. | ||
+ | And what I did was to take the various Vitamins D, there are a | ||
+ | number of metabolites. I took 1,25 dihydroxy-vitamin D, this is the | ||
+ | active metabolite, versus 25 hydroxy-vitamin D. That's the form | ||
+ | that the Vitamin D metabolite the sterol is stored in the body with | ||
+ | the D-bonding protein in the body fat. And it's stored for very long | ||
+ | times. Half life is a month, in some people a year for the storage | ||
+ | of 25-D. The body is very good at storing 25-D in between | ||
+ | manufacture of it. And then 24,25-D, 25,26-D are just | ||
+ | metabolites that occur when 1,25-D is deactivated. And they all | ||
+ | lie in the binding pocket. You can see they' | ||
+ | coincident, one on top of the other. The tails are a little bit | ||
+ | different, but the tails don't have very much to do with the | ||
+ | activation of the VDR, certainly with the transcription of the | ||
+ | immune mediators that we spoke about. | ||
+ | |||
+ | The only difference between all of these metabolites really is just | ||
+ | one alpha hydroxylation and that stabilizes helix 12 and that's | ||
+ | known to be essential for the binding to the promoters which allow | ||
+ | VDR to do its immune functions. | ||
+ | |||
+ | On the right-hand side for those of you that are more | ||
+ | technically inclined, I've got a molecule of Olmesartan as it's | ||
+ | bound into the VDR ligand binding pocket alongside 1,25-D, and | ||
+ | you can have a much closer look at the partial agonism which is | ||
+ | produced by that drug in the VDR. | ||
+ | |||
+ | So I'll just do a little bit of basic work here. We've got--on the | ||
+ | left we've got Vitamin D which is a secosteroid. And on the right | ||
+ | we've got corticosteroid. In this case it's prednisone. (And I've got | ||
+ | it upside down. And around the front. Okay, try the side. There | ||
+ | we are. Okay.) | ||
+ | |||
+ | So we've got the steroid rings here. You've got the five-member | ||
+ | ring, the six-member ring with the methane. Here you've got the | ||
+ | five-member ring, six-member ring with methane — it's | ||
+ | characteristic of all the sterols. And the only difference is that the bound between these two carbon which is present here on | ||
+ | prednisone and the corticosteriod has in fact been cleaved by an | ||
+ | electrocylic reaction, and that makes the Vitamin D a secosteroid | ||
+ | rather than a steroid. The interesting thing is that it actually gives it | ||
+ | a higher affinity for some of the nuclear receptors because there | ||
+ | are more degrees of freedom for this bottom ring because of the | ||
+ | inherent flexibility of these two double bonds and the single bond | ||
+ | down here. But that's the difference between Vitamin D and | ||
+ | prednisone, that one bond. | ||
+ | |||
+ | I'm going to skip this slide. The main thing to know about the | ||
+ | nuclear receptors is that we don't know a heck of a lot about them. | ||
+ | We're learning more as every month goes by. But the key two | ||
+ | words that I would use to describe how the nuclear receptors work | ||
+ | is redundancy and complexity. It's very, very complex. | ||
+ | |||
+ | The receptors combine as homodimers, they combine | ||
+ | heterodimers, | ||
+ | even with the Retinolic acid receptors, and all of these combine to | ||
+ | promoter proteins, which then will transcribe different genes from | ||
+ | the DNA. Because as you would all know the job of the nuclear | ||
+ | receptors is to transcribe the DNA into messenger RNA and then | ||
+ | into protein. | ||
+ | |||
+ | And here we have a closeup of the glucocorticoid receptor | ||
+ | Homodimer zinc fingers. That means there are two of these | ||
+ | glucocorticoid receptors bound together with the correct | ||
+ | promoters, and these zinc fingers are key to the location of the | ||
+ | parts of the receptor that actually target the gene and transcribes | ||
+ | the gene from the DNA spiral. | ||
+ | |||
+ | You can see here the backbone of the DNA spiral. The base | ||
+ | appears across the center. And you can also see the hydrogen | ||
+ | bond across the center too that holds the whole structure together. | ||
+ | That's a structure that you can download and play on your | ||
+ | computer at home, if you're interested. | ||
+ | 11 | ||
+ | |||
+ | The estimated affinity for the ARBs and statins into the nuclear | ||
+ | receptors was what surprised me. And I've got it tabulated here | ||
+ | and I'll just take a few data points off this and show you what we're | ||
+ | talking about. | ||
+ | |||
+ | Firstly, to answer Dr. Grimes' | ||
+ | statins, "Are statins analogues of Vitamin D?" he asks. | ||
+ | Well, here's the VDR and if there are going to be analogues of | ||
+ | Vitamin D they would have at least have to activate the VDR. And | ||
+ | Atorvastatin doesn' | ||
+ | does Fluvastatin. Lovastatin has a moderate affinity for the VDR. | ||
+ | Pravastatin at normal doses, that is essentially no affinity. | ||
+ | Rosuvastatin, | ||
+ | nmol Ki indicates that at normal doses Simvastatin would be | ||
+ | targeting the VDR. | ||
+ | |||
+ | So the first answer is you can't even talk about the statins as a | ||
+ | group because they' | ||
+ | And if you take another key receptor, the alpha-Thyroid receptor | ||
+ | over here, once again you see Atorvastatin, | ||
+ | affect. Lovastatin has a high affect, a very high affinity on the | ||
+ | alpha thyroid. Pravastatin and Rosuvastatin is essentially inactive. | ||
+ | Simvastatin again has activity in the thyroid subsystem. | ||
+ | |||
+ | So it's not a simple question are statins analogues of Vitamin D. | ||
+ | We've got to break down the degrees of freedom. We've got to talk | ||
+ | about which particular drug are we talking about. And then we've | ||
+ | got to look at does it have an affinity with Vitamin D. Simvastatin | ||
+ | does. So that's a good start. | ||
+ | |||
+ | In the case of the sartans, you've got a similar picture, except | ||
+ | the sartans tend to be more homogenous as a group with | ||
+ | Telmisartan being the only one that's out there on a limb with an | ||
+ | extremely high affinity for the VDR, but it acts as an antagonist for | ||
+ | the VDR. It also acts as an antagonist of PPAR-gamma and PPAR- | ||
+ | alpha. We wrote a paper last December that goes into that action | ||
+ | in more detail. | ||
+ | |||
+ | The Olmesartan that we are particularly interested in, has a | ||
+ | wide range of affect across all of the receptors, except the alpha | ||
+ | thyroid. It doesn' | ||
+ | is probably a good thing. | ||
+ | |||
+ | I've got similar charts of steroid activity in the key nuclear | ||
+ | receptors. I'll just leave that to the PDF and skip that at this point. | ||
+ | Hypothalamic-pituitary-adrenal axis | ||
+ | |||
+ | I'm going to look briefly at the hormonal control system in the | ||
+ | human body. It's pretty well characterized. This is the cortisol | ||
+ | access where you've basically got the glucocorticoid receptor with | ||
+ | a cAMP promoter. The promoter is known, the GCR as being the | ||
+ | transcriber of the gene is gone, and the first metabolite is the | ||
+ | corticotropin releasing hormone which is produced from the DNA | ||
+ | by the GCR with the cAMP promoter. But then changes to or is | ||
+ | converted to Pro-opiomelanocortin, | ||
+ | endorphin and ACTH. ACTH then catalyzes the conversion of | ||
+ | cholesterol into cortisol and then the cortisol goes around to the | ||
+ | top and binds into the glutocorticoid receptor. It also affects the | ||
+ | decomposition of corticotropin-releasing hormone, but you have a | ||
+ | basic feedback control system there. And the body tends to | ||
+ | control all of its hormones, all of its steroids very, very closely. | ||
+ | 12 | ||
+ | If you give a person cortisol and exogenously as an injection, | ||
+ | you upset the whole of this balance because you try and bypass | ||
+ | the feedback loop. That means you generally have to use much | ||
+ | higher doses than are present endogenously within the body itself | ||
+ | and you don't get the results you necessarily expected. | ||
+ | |||
+ | Now slightly more complex metabolism is the Vitamin D steroid | ||
+ | metabolism and this is pretty well up to date, I think as of October | ||
+ | the 23rd [2006], a compendium of everything that's being | ||
+ | published and is reliable on the way that the body regulates the | ||
+ | hormone called Vitamin D, 1, | ||
+ | activates the VDR, what allows the transcription of the | ||
+ | antimicrobial peptides and the toll-like receptors. | ||
+ | |||
+ | And we start at the top from 7-dehyro-Cholesterol. All of the | ||
+ | Vitamins D are produced endogenously in the body from 7- | ||
+ | dehydro-Cholesterol. Typically, we think of a vitamin as being | ||
+ | something that you have to ingest in order for the body to work | ||
+ | properly. But that's not the case with Vitamin D. All of the Vitamins | ||
+ | D can be produced from 7-dehydro-Cholesterol and that seems to | ||
+ | be the normal way that the body produces it. | ||
+ | |||
+ | The first step to pre-vitamin D is typically thought to involve UVB | ||
+ | energy. However, the electrocyclic reaction — conrotatory | ||
+ | electrocyclic reaction — is found elsewhere in nature, catalyzed by | ||
+ | enzymes. So there' | ||
+ | still have to go looking for. Do we need UVB or do we need | ||
+ | enzymes? Big question mark over the whole concept of whether | ||
+ | Vitamin D is a vitamin or whether it is just a hormone precursor. | ||
+ | |||
+ | And then pre-vitamin D the electrons rearrange slightly in a | ||
+ | sigmatropic shift to create vitamin D which then is hydroxilated to | ||
+ | 25-hydroxyvitamin, | ||
+ | the p-450 enzymes or CYP2R1. And then that, monohydroxy, | ||
+ | converted to the dihydroxy by CYP27A1 again — a heme-related | ||
+ | enzyme — or by CYP27B1. And B1 is primarily expressed in the | ||
+ | macrophages, | ||
+ | 25-D to 1,25-D, but it doesn' | ||
+ | system and that's the one which is most active in the immune | ||
+ | system. | ||
+ | |||
+ | Then finally, 25-D is degraded into an inactive form by CYP24 | ||
+ | and CYP3A4 which are up regulated by the VDR. So if there' | ||
+ | much 1,25-D, the VDR upregulates the inactivation pathway and | ||
+ | that upregulation is cancelled or offset by androgen activity: | ||
+ | testoterone, | ||
+ | gamma and 1,25-D are so closely coupled together because | ||
+ | interferon gamma stops 1,25-D from being degraded. It stops the | ||
+ | enzymatic feedback there and also by PXR. And when the VDR is | ||
+ | activated you have innate immunity and you have down-regulation | ||
+ | of the parathyroid hormone by the 1,25 dihydroxy-D — 1,25 | ||
+ | dihydroxy-vitamin D — and then the parathyroid hormone in | ||
+ | conjunction with the calcium sensing receptor which is in the | ||
+ | kidneys sorts out the body's calcium homeostatis and then the | ||
+ | body's calcium homeostatis feedbacks into the expression of | ||
+ | CYP27A1. And there' | ||
+ | steroid metabolism. | ||
+ | |||
+ | Not simple by any means, and actually not unreasonable if you | ||
+ | consider that the immune system would have had to adapt through | ||
+ | evolution in many stages and that's really what we're seeing as we | ||
+ | dig further and further into the way that the Vitamin D metabolism | ||
+ | works in man. | ||
+ | 13 | ||
+ | Well, up on the top left here I've got a configuration of | ||
+ | dexamethasone as it stops into maximum affinity and to the | ||
+ | glucocorticoid receptor binding pocket — ligand binding pocket. | ||
+ | And the backbone is in purple. Here is the fluorine atom [green] | ||
+ | and the oxygen is obviously in red. And on the lower right I've | ||
+ | got 1,25D superimposed on that, with a green backbone, | ||
+ | showing how it binds into the GCR and it binds into exactly the | ||
+ | same ligand binding pocket. There is no doubt that 1,25D | ||
+ | displaces cortisol and dexamethasone from the GCR in a | ||
+ | concentration-dependent manner and vice versa of course. | ||
+ | |||
+ | So when you factor this knowledge in, what happens when the | ||
+ | immune system run haywire and 1,25D levels build as we see in | ||
+ | clinical practice? | ||
+ | |||
+ | 25-D and 1,25-D go into the glucocorticoid receptor and | ||
+ | intercede — make this whole hormonal feedback system break | ||
+ | down — and you end up with patients who have adrenal | ||
+ | insufficiency which is very, very common in these Th1 diseases. | ||
+ | However, I point out that increasing the dose of cortisol to try | ||
+ | and cope with the adrenal insufficiency is the incorrect way to go | ||
+ | about treating the problem. It has to be attacked at the actual | ||
+ | cause by lowering the 25-D, the ingested Vitamin D, and the | ||
+ | 1,25-D, the inflammatory load. | ||
+ | |||
+ | However, the Vitamin D also competes for the alpha-1 Thyroid | ||
+ | binding pocket, and hypothyroidism is very common in these Th1 | ||
+ | diseases. Here's T3. You can see the three atoms here in green. | ||
+ | T3 as it binds into the alpha-1 Thyroid receptor. And here we | ||
+ | have 1,25D competing with T3 for the ligand binding pocket of | ||
+ | the alpha-1 thyroid receptor. And as you can see they will | ||
+ | displace each other from the receptor in concentration and | ||
+ | affinity-dependent manners. | ||
+ | 14 | ||
+ | |||
+ | Vitamin D in bone remodeling I'll skip in this group because I'm | ||
+ | running behind time. | ||
+ | |||
+ | But I do want to briefly consider the public health consequences | ||
+ | regarding Vitamin D as a vitamin. | ||
+ | |||
+ | If we look back to the 1923 nobel oration the 1923 nobel | ||
+ | prizes given for the elucidation of the function of the sterols in | ||
+ | particularly what we know as Vitamin D in the body and if you look | ||
+ | at the nobel oration, you'll find that there really no concept of | ||
+ | vitamin in it. Originally, the concept was this is a sterol. This is a | ||
+ | sterol, a secosteroid, | ||
+ | |||
+ | Sometime during the 20th Century we began to view | ||
+ | Cholecalciferol as a vitamin rather than focus on its steroidal and | ||
+ | hormonal activity. And when we started putting this in the food | ||
+ | chain, in a futile attempt to eliminate the rare disease rickets — | ||
+ | rickets now turned out to be in the latest, very comprehensive | ||
+ | studies to be eliminated only by calcium and phosphorous in the | ||
+ | diet. But we put it into the food chain back starting about 1950s to | ||
+ | try and eliminate rickets and we haven' | ||
+ | although the incidence has dropped. | ||
+ | |||
+ | As physicians, many of you who are physicians would certainly | ||
+ | know the side effects from the administration of steroids. The | ||
+ | Centers for Disease Control in the USA says that the US is heading | ||
+ | towards half of all US seniors being diabetic by the year 2050. | ||
+ | That is exactly the track that the US population is on right now. | ||
+ | And we all know about obesity. | ||
+ | |||
+ | Here's an article from earlier this week. "U.S. Children grow | ||
+ | bigger bellies," | ||
+ | |||
+ | Actually over here [left column under picture] it's interesting. | ||
+ | Canadians getting fatter but more slowly. But what they found was | ||
+ | that this particular study that Rochester School of Medicine found | ||
+ | was that ten and a half percent of boys and girls had too much | ||
+ | abdominal fat in1999, as measured by waist circumference. This | ||
+ | included seventeen and a half percent of boys and girls in 2004. | ||
+ | In just five years, the obesity rose sixty-five percent. | ||
+ | |||
+ | Now I don't think McDonalds sales rose sixty-five percent in | ||
+ | those same five years from 1999 to 2004. There were other | ||
+ | factors at play. Obviously I have my theories as to what those other | ||
+ | factors are. | ||
+ | 15 | ||
+ | Here they are. These are the US experience and I've put this | ||
+ | slide together because in Australia you've all been pretty well | ||
+ | shielded at this point from supplementation of the diet with | ||
+ | exogenous Vitamin D, artificial Vitamin D. | ||
+ | |||
+ | In America, milk and yogurts are fully supplemented with | ||
+ | Vitamin D. If you have two glasses of milk a day you get the entire | ||
+ | supposed RDA of Vitamin D, and we find that that is more than | ||
+ | enough to take the levels of 25-D in the body into | ||
+ | immunosuppressive range. | ||
+ | |||
+ | Cheese, particular cheese slices that are intended for kids' | ||
+ | meals, for kids' lunches, are fortified with Vitamin D in the US. | ||
+ | Kraft Macaroni and Cheese and all of the cereals, all of the | ||
+ | breakfast cereals for kids, they' | ||
+ | kids can't get away from this stuff. And now of course orange juice | ||
+ | is fortified with Vitamin D to make it really good for you. | ||
+ | |||
+ | That's the experience in the United States. It's a very sad | ||
+ | experience, but that's what's happening at the moment. And I put | ||
+ | at the bottom right there a bottle just to remind us, but the calcium | ||
+ | for Vitamin D is so often prescribed to patients who present with | ||
+ | these inflammatory disease presentations, | ||
+ | also have osteopenia. And that's counterproductive because the | ||
+ | people that need the Vitamin D least are the ones that get | ||
+ | supplemented and that's purely because clinical medicine is not | ||
+ | measuring the correct metabolite. They need to measure 1,25 | ||
+ | dihydroxy, the active metabolite, as well as the inactive metabolite. | ||
+ | |||
+ | So let's go on to talk about the pathogens which is the other | ||
+ | half of the disease equation. | ||
+ | |||
+ | Now we've known for sometime that there are bacterial | ||
+ | pathogens that are capable of living in the phagocytes. This is | ||
+ | from a study " | ||
+ | tissue from Patients with Sarcoidosis," | ||
+ | came out. And it showed bacteria staining inside the phagocytes. | ||
+ | The authors inferred that these bacteria were rickettsia and they | ||
+ | may very well have been, but the point was bacteria can survive | ||
+ | inside the phagocytes. That is a mind boggling concept. The | ||
+ | phagocyte is supposed to phagocytose they are supposed to | ||
+ | breakdown the bacterial DNA and render the bacteria harmless. | ||
+ | Protection from Phagocytosis — Biofilms | ||
+ | |||
+ | This is a photo from the paper, the review paper, The Microbial | ||
+ | Resistome. This talks a lot about horiozontal transfer of DNA. | ||
+ | Search for it PubMed or in Google, The Microbial Resistome. It's | ||
+ | brillant. | ||
+ | |||
+ | The reason I put it on there is to show biofilms. This is from the | ||
+ | Centers for Disease Control and it shows how Staph aureus | ||
+ | produce biofilms which are a sticky looking substance. They | ||
+ | secrete sticky looking substances called biofilms. | ||
+ | |||
+ | And that's what we see associated with these tiny bacteria that | ||
+ | are found in the inflammatory diseases. | ||
+ | 16 | ||
+ | The Wirostko Studies were performed in the late 1980s at | ||
+ | Columbia University in New York by the Wirostkos, the family of | ||
+ | Wirostkos and another collaborator. And what they did was quite | ||
+ | unique. They took patients who had Crohn' | ||
+ | rheumatoid arthritis, and sarcoidosis and they used transmission | ||
+ | electron microscopy to examine the phagocytes and they stained | ||
+ | the bacteria. | ||
+ | |||
+ | They were particularly interested in seeing whether it was | ||
+ | possible for phagocytes to become infected. And they found that | ||
+ | all of the phagocytes — monocytes, macrophages, | ||
+ | and neutrophils — were all infected by these tiny little L-form | ||
+ | bacteria that were first described in 1934 by ME Kleinberger | ||
+ | Nobel of the Lister Institute. | ||
+ | |||
+ | And we have here a single isolated coccoid about .01.015 | ||
+ | microns diameter. What am I saying, microns? Nanometers in | ||
+ | diameter. Ten to fifteen nanometers diameter. | ||
+ | |||
+ | And then we have a kidney-shaped colony which in itself I haven' | ||
+ | counted these but they must well be over a hundred individual | ||
+ | coccoids in there, string of about a dozen coccoids in here, and | ||
+ | another gaggle of coccoids there, and another artifact of stained | ||
+ | bacterium there. These are tiny little bacterium. | ||
+ | |||
+ | And what was particularly interesting about this photo was this | ||
+ | crenation in the nucleus which doesn' | ||
+ | nucleus, part of the nucleus is actually breaking off as shown by | ||
+ | this dark arrow. It's shown by the big arrow. And that nuclear | ||
+ | activity was close to the largest colony of bacteria in this case. | ||
+ | Every one of these photographs that they took showed infection | ||
+ | and every one of the photographs that they took show slightly | ||
+ | different physical manifestations of an infection in some case vastly | ||
+ | different. But the two things that were common throughout them all | ||
+ | was a lot of transparent and semi-transparent material like this, the | ||
+ | biofilm, and also the tiny, tiny coccoids. | ||
+ | |||
+ | Now is a phase contrast optical microscopy. This is done with a | ||
+ | Bradford Microscope. It has also been done with quite inexpensive | ||
+ | microscope, microscopic equipment. I'll just stop it there, pause it. | ||
+ | And what we've got is these tiny little threads, thread-like | ||
+ | appendages, which are made of a translucent tubular material | ||
+ | which stains with fluorescent antibodies for bacterial RNA. (How | ||
+ | did I get back there?) And these are exiting a crenating red cell in | ||
+ | this case. | ||
+ | |||
+ | This is a technique which was devised by Andrew Wright in | ||
+ | Northern UK where he takes pinpricked blood, puts it between a | ||
+ | slide, seals air out with vaseline and then allows the blood to | ||
+ | degrade a period of six to thirty-six hours. And as you can see this | ||
+ | is a monocyte that has disintegrated. You can see these tiny long | ||
+ | forms that have no analogue in pathology. There is no explanation | ||
+ | in pathology for what these are, except of course that they are the | ||
+ | bacterial L-forms. | ||
+ | |||
+ | (Video continues of biofilm moving very different from Brownian | ||
+ | elements moving in background, and static cells.) This particular | ||
+ | picture there is a bacterial L-form here which is going to do a | ||
+ | linear movement toward the bottom, just to show those of you that | ||
+ | think it's all Brownian in motion. It is not. It's going to gradually work to the bottom, as I speak, but this equipment, the equipment | ||
+ | |||
+ | that was used to produce this photograph, was bought off E-Bay, | ||
+ | very, very simple analogue microscrope x400 and a standard | ||
+ | camera with computer software to amplify up the size of the | ||
+ | image. So this little fellow will go off the screen and I'll just allow it | ||
+ | to refocus to show you that it keeps going down and eventually | ||
+ | disappears totally from the field of view. There is Brownian motion | ||
+ | visible and something like Brownian motion in the other particles | ||
+ | there, but this thing seems to know where it's going. | ||
+ | |||
+ | Okay. So what do our antibiotics do? Our antibiotics go after | ||
+ | the bacterial ribosomes. The 70S bacterial ribosome is in two | ||
+ | halves, the 30S, 50S subunits. The 30S, the MRNA is translated by | ||
+ | the helical structures at the top. You've got the tRNA here which | ||
+ | donates the amino acids to the growing protein chain. And then | ||
+ | the protein leaves the bottom of the 50S section. And the | ||
+ | antibiotics we use target different areas of the ribosomes. | ||
+ | |||
+ | If we look up at just the 30S subunit, what we've got is up top | ||
+ | these helical structures which involve with advancing the mRNA as | ||
+ | it is decoded. | ||
+ | |||
+ | And right sitting there are the molecules of tetracycline in the | ||
+ | various locations that they bind with quite strong affinity. | ||
+ | |||
+ | This work is from the Max Plank Group in Hamburg, Germany. | ||
+ | Max Plank Ribosome Group. | ||
+ | |||
+ | And so minocycline, | ||
+ | use inhibits — it doesn' | ||
+ | translation of the mRNA at that point, the top of the 30S ribosome. | ||
+ | |||
+ | Then the 50S ribosome, you've got the protein exit channel here | ||
+ | at the bottom and in red here, that's where the macrolides bind the | ||
+ | erythromycin and the azithromycin that we use. And just above | ||
+ | that is where the clindamycin binds. If you'll remember that's the | ||
+ | third antibiotic we use in the longer term cocktail to totally get rid | ||
+ | of the bacterial load that the patients are carrying. | ||
+ | |||
+ | And the important thing to note from the animation is that each | ||
+ | of these antibiotics is symbiotic. None of them interfere with each | ||
+ | other. The addition is linear and it's symbiotic. | ||
+ | 18 | ||
+ | Now what about the actual pathogens? Still everybody wants to | ||
+ | know well what species is it; what species causes these infections? | ||
+ | The answer is: You're dealing with a chronic infection building | ||
+ | over a lifetime. You're not going to be dealing with a species. | ||
+ | You're going to be dealing with massive amounts of horizontal | ||
+ | transfer of DNA, particularly of plasmids. | ||
+ | |||
+ | And now that we know what the genomes look like we've got | ||
+ | some bacteria, for example, borrelia burgdorferi, | ||
+ | nearly half its genome on 21 self-replicating plasmid subunits. It is | ||
+ | most definitely going to be sharing plasmids. And even common | ||
+ | species like staph epidermidis have ten percent of the DNA split | ||
+ | over six self-replicating plasmids. Those plasmids can easily be | ||
+ | shared. They are not targeted by antibiotics and they are only | ||
+ | targeted by the innate immune system and then only weekly. They | ||
+ | are going to accumulate over time unless cleared by the immune | ||
+ | system and you're going to be dealing not with UNI-microbial | ||
+ | disease but with a POLY-microbial disease. A combination of the | ||
+ | infectious history of the individual including both viral and | ||
+ | bacterial pathogenic challenges. | ||
+ | |||
+ | And here is a paper from the National Academy of Sciences, | ||
+ | 2004, where two plasmids from bacillus anthracis were transferred | ||
+ | to the genome of bacillus cereus and a patient died very quickly as | ||
+ | a result of that. They actually were wondering why the patient had | ||
+ | died from bacillus cereus until they noticed that, that particular | ||
+ | genome had also acquired at some point the two plasmids from | ||
+ | bacillus anthracis. And those two plasmids, one conveys the ability | ||
+ | to evade phagocytosis, | ||
+ | And particularly interesting over here is bacillus thuringiensis. | ||
+ | That's used as an insecticide. That's sprayed onto our crops as an | ||
+ | insecticide. That's very close in phylogeny. | ||
+ | |||
+ | Now this is survival of mice challenge with that particular hybrid | ||
+ | of cereus anthracis plasmids. And normally it's harmless. That's | ||
+ | anthracis itself [refer to chart] whereas the hybrid kills more quickly | ||
+ | than anthracis itself. The horizontal transfer of DNA is absolutely | ||
+ | key to understanding the pathogens in these diseases. | ||
+ | 19 | ||
+ | My final slide is work from Rolf Zinkernagel who together with | ||
+ | Peter Daughtery at John Curtain did a lot of study on antibody | ||
+ | presentation and got the 1996 Nobel prize for it. | ||
+ | Now Rolf has dedicated his life subsequent to the Nobel to | ||
+ | showing that autoimmune disease is not due to antibodies | ||
+ | themselves. And I had a very good long discussions with him at | ||
+ | Karolinska [DMM 2006]. | ||
+ | |||
+ | And this particular experiment which is a recent publication by | ||
+ | his, 2006, they injected lymphocyctic choriomeningitis virus into | ||
+ | newborn mice, into the brain of newborn mice. And what they | ||
+ | found was that the virus appeared to be cleared and it couldn' | ||
+ | detected by normal techniques, but it was clearly persistent in the | ||
+ | brain. Because when those mice were challenged later in life with | ||
+ | either a slightly different virus or with the same virus, then there | ||
+ | was a very energetic immune reaction and the mice died. | ||
+ | Whereas, if the mice had been initially challenged later in life after | ||
+ | the adaptive immune system had started to work properly then they | ||
+ | were able to cope with both the initial and subsequent challenges | ||
+ | from the virus. | ||
+ | |||
+ | Because, you see, mice are just like human beings. When | ||
+ | they' | ||
+ | adaptive immunity running. In the case of mice you can see the T | ||
+ | cells starting to become active here at about day seven in their | ||
+ | lifespan. In humans, it's a little bit longer than that. It's in weeks. | ||
+ | But it takes a while. And during that time the infant is only | ||
+ | protected by the innate immune system. And what happens in that | ||
+ | time is quite critical. | ||
+ | |||
+ | And what Rolf's group has shown is that you can have an | ||
+ | occult virus which is persisting in the brain through life which is | ||
+ | later activated into an extremely energetic and pathogenic state. | ||
+ | That is a model for what we're also seeing with the bacterial | ||
+ | pathogens in these chronic diseases. | ||
+ | |||
+ | So there we are. Thank you very much for listening to the talk. | ||
+ | And we'll see if there are any questions. | ||
+ | |||
+ | {{tag> | ||