Dr. William Chamberlin: 2015 Crohn’s Research Symposium Introduction
Ok, I’m Dr. William Chamberlin and I want to thank you all for coming here. First of all, I want to introduce the lady who made this possible, Stacey Sturner. On behalf of our panel of world-renowned medical experts, welcome to today’s Symposium on Crohn’s Disease. As some of you know, my 7-year-old son Jackson was diagnosed with Crohn’s exactly one year ago (actually this weekend). It has been quite a year. There have been lots of highs and lots of lows. Planning this event, however, has been an absolute peak for our family, as what you are about to hear has filled us with hope. Before we get started with the presentation I would like to thank several people for their help in making today possible. Julie Doyle, who is joining us from New York, Lillian and Donald Lurye, Jessica and Benjamin Felch, Michelle Bernstein, Jenny Ginther, Dawn Snyder, Craig Hughes, and most importantly my husband Barry who volunteered me in the first place. Thank-you. Also a big shout out to our sponsors, CJE Senior Life, Jewish Child and Family services and Townsend Financial. So with no further ado, it is both my honor and privilege to turn you back to Dr. William Chamberlin.
Well, Thank you very much and Thank you for being here. For those of you with Crohn’s, have family members with Crohn’s or know somebody with Crohn’s, I think you are going to be very interested in what we have to say. I’m gonna try move through my introductory talk as fast as possible because the real substance comes from the far reaches of the globe, New Zealand, and the UK, so we’ll get started. First of all, why did we organize is the symposium? To publicize our latest discoveries, to gain the needed support for what needs to be done. We want to change the concept or at least modify it to a better treatment approach and we want to cure Crohn’s disease. We just don’t want to make patients feel better. We want to cure the disease. And after you hear what we have to say, you see why I’m hopeful now, really for the first time. I think we are on to something. It’s not to be one simple treatment, may not be something that we’re talking about today and I think it’s in that right direction.
But most importantly, we gotta get our story out there. Most physicians, most laypeople, most people do not know what we’re doing. They may have heard of it but have different conceptions about what’s really going on. So, that having been said, when you leave here I would like you do to just walk out of here with what a few simple facts. One, Crohn’s disease is a syndrome involving innate immune deficiency. It’s an innate immune deficiency disease it predisposes to microbial infections and Mycobacterium paratuberculosis or MAP, infects blood macrophages. Common sense says it should be treated and we will find out whether that will make Crohn’s patients better or not. The trouble is how to treat it, because it’s very difficult to treat. Now, it would be great if everybody here knew everything there was about Crohn’s disease, immunology, and atypical mycobacteria. Atypical mycobacteria being defined as mycobacteria that are not tuberculosis or non-tuberculosis mycobacteria and when you read on the Internet that will be referred to as NTMs.
Okay now tuberculosis, which most people know something about, that’s just a different animal. It’s a different species than MAP or other atypical mycobacteria, it acts differently. The treatment is different. (There are) A lot of similarities, we can learn a lot from what we know about tuberculosis, but don’t think that they’re identical.
So a few quick concepts for how to better understand the current situation, and clearly the current situation is that this is very controversial and we’ll get into why it’s so controversial very briefly. The first thing let’s talk about simple definitions. Etiology: That’s the cause of the disease. Pathogenesis: that’s the description of the disease processes that are played out at the molecular and cellular level. For Crohn’s disease, the etiology is a mycobacterial infection. That’s what I am submitting to you right now. The pathogenesis has to do with damaging inflammation.
This is very important as current therapies are really focused on treating the pathogenesis, controlling the inflammation, and that’s all very valid. We want to direct at the cause of Crohn’s disease. If we’re successful in doing that I think we can move towards a cure. Now I’m going way out on a limb, because we are not there yet, and it may not occur in my lifetime, I’m hoping it can occur when the next five years and you’ll see why as we go on with this.
The next concept that I want to touch on is that of paradigms. I think the understanding of what paradigms are, and how powerful they are, will help explain the controversy that is surrounding this situation. A paradigm is that pre-formed mindset that we all have, through which we interpret and give meaning to what we see around us. So if I were to look at some data, and my evil twin brother who is just as logical or illogical as I am, were to look at the same data using different paradigms, we may walk away interpreting the meaning of that completely differently even though we could use the same words to be describing it. So it’s your mindset, it’s how we view things, how we interpret and view things.
Now, what are the paradigms that have heavily influenced the field of Crohn’s disease? I will mention three of them. The first is the autoimmune paradigm and that says that the immune system has just turned on the body. It is attacking molecules that are made by the self; It’s an auto-immune process. That has dominated the thinking that has directed treatments for the last 50 or 60 years. A lot of people that are researching this, no matter what they think the cause is now, are moving away from the autoimmune theory primarily because there was no evidence for it ever, although it was a very reasonable, plausible theory to put forward 50-60 years ago.
That leaves us with two other paradigms both related to bacteria. One is that a dysbiosis, which considers the imbalances in the microbial ecosystem that occurs in the gut that is seen in Crohn’s disease, as influencing the mucosal immune system in such a way that you get chronic inflammation. Then the third paradigm is that of the more old-fashioned simple infectious disease. There is a specie or a species of bacteria out there that infects the host, that causes inflammation in the gut, and it that inflammation, which affects the microbiota causing the imbalances. So the dysbiosis theory would be suggesting that the primary cause is within the gut echo system. Whereas, the infectious disease theory says that the changes in the microbiome are secondary to a primary infection elsewhere. Now, we’re gonna be saying that primary infection occurs in the cells of the innate immune system, the dendritic cells in the macrophages which are both at the center of the immune network and are also the primary effector cells. Okay, one other thing, paradigm shifts do not occur easily. It is very difficult to shift your mindset and how interpret your worldview and we shouldn’t, but it needs to be done.
Now, I was going to go on with here’s my take on it, and this is an email that I got I’ll just read it. It is well described that a dysbiosis in the gut microbiome leads to inflammation in the gut via an increase in TH17 and TH1 cells and a decrease in the T reg cells and IL-10. Now that’s a little too involved probably, but this in turn leads to increased permeability of the gut mucosa and the systems effects beyond pathology. If I was approaching this with the dysbiosis paradigm, I would be saying “hey, we’re really onto the cause and it lies within the microbiota.” I don’t and I say that actually what they’ve described, I agree with all of that, but that has to do with pathogenesis, the disease process is being played out on the molecular and cellular level.
So to get a better understanding of Crohn’s disease and where it comes from a quick historical walk-through is in order. In 1882, Robert Koch identified the cause of consumption, that being Mycobacterium tuberculosis and that being primarily a pulmonary disease. Within 10 years, they noted that TB could also occur in the gut, and it will look like the Crohn’s disease syndrome. So yes, intestinal tuberculosis is a cause of the Crohn’s disease syndrome. The issue is that we identify the presence of TB at that time. Within another 10 years at the turn of the 20th century, they were seeing this chronic inflammatory disease of the bowel but they couldn’t see TB, so the question is, is this TB or is this some other microbe? In 1913, Thomas Dalziel wrote a paper suggesting that perhaps this disease is related to Johne’s disease, which is caused by a species of mycobacteria that we now call Mycobacterium avium paratuberculosis.
So for the first third of the 20th century, the question was “hey is this intestinal bowel disease TB or is it another mycobacteria or is it some other microbe but is an infectious disease?” Then in 1932 Crohn, Oppenheimer and Ginzburg wrote their paper. Very recently, they said “hey, we have identified the causal agent.” Let’s take a step back. Let’s not assume anything, let’s study this disease in its own right and so let’s open our minds, very reasonable. Unfortunately, the medical community took what they said and interpreted as we look for an infectious disease, we couldn’t find it. Therefore, it isn’t, which is totally different.
Now moving forward it to you the decades past the 1950s came and the hypothesis was put forward that Crohn’s disease is a psychiatric disease. This was the Golden age of psychiatry. The 1960s brought the autoimmune hypothesis. This is very plausible because we had inflammation. It was chronic. We didn’t know what was causing it. Perhaps immune system was turning on the host, but like I already said, we’ve moved away from that being, it’s not a strong hypothesis as we once thought, and we’re left with the dysbiosis in the infectious disease. Now, I’ve latched on just to the infectious disease. Also, the immune deficiency that goes along with it. Now you can define an immune deficiency as any immune system that allows an infection that most people can handle as a relative immune deficiency. So that gets into sort of a circular argument. That’s fine, no matter what some people always returned to the infectious disease theory.
I believe that one of the beginning, extremely high points was in 1982 when Walter Thayer and Rod Chiodini took a bowel specimen from little 12-year-old African-American girl, and at that time the party line was that African-Americans didn’t get Crohn’s disease or was very rare. Well, they grew, Rod grew, what turned out to be Mycobacterium paratuberculosis in pure culture. He gave it to a baby goat who developed a chronic inflammatory disease that could pass for Crohn’s disease and that caused a lot of excitement. For those who believed in MAP as a causal agent will say, hey that actually is a modified Koch’s postulate.
Okay, now if you don’t believe that that MAP is a causal agent, the argument comes down to, all you’ve done is find a known goat pathogen that happened to be in a human at the time you happen to have had Crohn’s disease at the time. And you fed this known goat pathogen to the goat and he got the disease. So you can argue things very logically with different paradigms. Now, nevertheless, a lot of people got excited and a lot of laboratories got involved some very large influential laboratories, some smaller not so influential laboratories. The problem was that these no matter how big or famous you were. You didn’t necessarily know how to handle and grow and study MAP; Because MAP is not tuberculosis and a lot of negative papers came up saying “we’ve looked, MAP is not there in Crohn’s disease.” And then there were papers saying, “actually, we’ve looked and it is.” So the controversy began. Is MAP there or isn’t it there and along those lines that sort of defines the next 20 to 30 years.
Right now, looking back, I look at certain key developments that I certainly wasn’t smart enough at the time to even read the papers probably. I go back to 1976, Anthony Segal said that whatever’s causing Crohn’s, and he didn’t put forward what the cause was, he said there is an immune deficiency associated with it. He said that because neutrophils, which are a key molecule and key cells of the innate immune system, did not migrate properly in Crohn’s patients. Then over the next several decades, he showed that the problem wasn’t with the neutrophils, but it was with the macrophage, these other key cells of the innate immune system.
The next big development, I believe that was really of historical significance, was the fact that we were able to sequence the human genome. With that, they started doing genome-wide association studies on different diseases, one of which was Crohn’s disease. They could take 100,000+ patients with Crohn’s and compare those to a bunch of normal controls. They saw, which single nucleotide polymorphisms, which gene mutations, put you at risk, was associated with Crohn’s. What they came up with was 70 or 80, and I don’t know what the number is now, snipped single nucleotide polymorphisms that put you at risk of getting Crohn’s. They didn’t give you Crohn’s, but it put you at risk. These were involved in genes that were associated with the innate immune system. So here we had a relatively agnostic study implicating innate immune deficiency with Crohn’s disease. Oh and by the way, these same genes put you at risk of getting Mycobacterium Tuberculosis and Mycobacterium Leprosy; now that really fit into the concept that these other species of Mycobacteria along with perhaps another Mycobacteria that we don’t know about, is a causal agent of Crohn’s. That along with some other technology, some of which you will hear today makes us submit that Crohn’s disease is a disease of the innate immune deficiency predisposing to intracellular infections of the dendritic cells and macrophages, resulting in the dysregulated immune responses, persistent infection of macrophages and chronic inflammation, and on that statement that’s pretty broad but I think that covers a lot.
This is how most doctors will organize their thoughts when studying a disease and I will talk about etiology. We’re saying that the etiology is an infection of the immune system. MAP is one of the causes that leads to damaging inflammation, which is a disease process, that then causes tissue damage, clinical symptoms, and signs. The treatment then right now is directed primarily at controlling the inflammation. That’s a good treatment, but it would be better if we could actually get the causal agent.
What are the current therapies? I’m not going to spend a lot of time going through them, I just want to point out that the accepted treatments include antibiotics of metronidazole and ciprofloxacin which are great antibiotics for a typical mycobacterium. I use them in my treatments. I’m going to throw up (some pictures); maybe you recognize yourself in here. I’m not to spend any time going through this, but this is Crohn’s disease. Okay, this is Crohn’s disease, and you know more than I about this and what you all go through. Now it’s not just in the bowel, it’s extra-intestinal, perianal problems or serpiginous ulcers. This is also a Mycobacterium this is a big skin lesion you get with Crohn’s.
I used to see a lot of this in Papua New Guinea. These weren’t Crohn’s patients that I was treating, they were patients infected with Mycobacterium Ulcerans, another species of Mycobacteria. I predict that if we come up with a good diagnostic test, a really good one, you can find Mycobacteria involved with this and I suggest that you look underneath the skin faults right there at the edge of the ulcer. That’s where you can be finding it. The way we used to treat that is we just take a scalpel, scrape the subcutaneous fat away and then do skin grafts. I’ve done hundreds of those. So, anybody, that’s into that stuff, please get involved. I’d, I bet you my right arm, I’m correct. Crohn’s disease gives you extra-intestinal manifestations also.
So I said I’d talk a little bit about immunology and I’ll give you the two-minute course on immunology. First of all, how do microbes cause disease? They either do it through overwhelming reproduction, they either secrete toxic molecules or they elicit an immune response which damages the host. That is how Mycobacteria cause disease. So what is the immune system? Well, you’ve heard me talk about the innate immune system and the adaptive immune system. That’s probably purely artifactual; there is just one immune system, but it does help somewhat. Looking at the phylogenetic tree of life as we evolved from single cell organisms into the metazoans that we are, the multicellular organisms, we fought off the microbial world that was trying to use us as an energy source, i.e. use us as food. By developing the immune system, for most of life on this planet, the innate immune system is good enough, but under the increasing evolutionary pressures of the microbial world we had to find a way for our immune systems to respond faster than just through simple adaptation every time we produce from one generation to the next.
We started using receptors that were based on the immune globulin superfamily which can adapt at hyper speed. The cells of the immune system, of the innate immune system, are basically these myeloid progenitor cells but also include the natural killer cell. Then this was the innate immune system. Now it is from this cell or progenitor from it, you had differentiation into cells that served another function and those were your immune globulin cells that made up the adaptive system, which are the antibody secreting cells, memory cells, and your TH cells, of which there are different variations, that secrete cytokines that feedback and help inform and integrate the adaptive systems.
So it really becomes one big immune system. What we have found is that the Crohn’s disease is associated with the deficiency in the innate immune network, and that’s how it is. Think of this is a big network disease. Now one other point, the speakers here all act independently of one another. We know each other. We communicate with each other. We support each other but fundamentally we don’t think in lockstep with each other so what I’ve just said, you may hear variations from the others. I don’t have any clench on the truth by any means. That’s why this is a research symposium; we’re trying to move forward. We’ve got the following speakers coming forward. Professor Michael Collins will now talk on MAP in animals and then we got a surprise speaker that graciously volunteered to speak at the end; that’s David Rubin, who’s one of the key gastroenterologist at the University of Chicago, and I really do appreciate him coming.