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Bacteriophages are viruses that infect bacterial cells and either kill the cells or cause them to mutate. These fascinating bacteria-killing viruses are being studied for their ability to improve antibiotic sensitivity and treat a variety of different types of infections, including pulmonary infections.
Dr. Paul Turner and Dr. Benjamin Chan have been studying bacteriophages at Yale’s Paul Turner lab for years, and in today’s episode of New Frontiers, they talk with Dr. Fitzgerald about the wide and fascinating world of bacteriophages.
In this podcast you’ll hear:
- What a bacteriophage is
- Mechanisms by which bacteriophages work to kill bacteria while leaving the rest of the ecosystem unharmed
- How bacteriophages improve a bacteria’s antibiotic sensitivity
- History of bacteriophage research
- Use of bacteriophages to manipulate the lung microbiome to make it more antibiotic sensitive
- Use of bacteriophages in pulmonary infections, especially cystic fibrosis
- How phages target biofilms
- Need for more research on healthy microbiomes
- Relationship between an overabundance of certain phages and inflammatory bowel disease (IBD)
- Contraindications and side effects of phage therapy
- Potential of phage therapy in treating Lyme disease
- Best way to deliver phages for specific parts of the body (intestines, lungs, etc.) and the efficacy of OTC bacteriophages sold as part of probiotic blends
- How patients interested in phage treatment can contact Chan and Turner
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Dr. Paul Turner, PhD
Professor of Ecology and Evolutionary Biology, Yale University
- Mail: paul.turner@yale.edu
- Web: http://turnerlab.yale.edu/
Dr. Benjamin K. Chan, PhD
Associate Research Scientist, Yale University
- Email: b.chan@yale.edu
- Web: http://www.benjaminchanphd.com
- Instagram: @AspiringAspirant
- Twitter: @AnotherBenChan
Dr. Kara Fitzgerald: Hi, everybody, welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine and today is no exception. Before I introduce my guests, I just want to say if you like what you’re hearing, please consider swinging over to iTunes and leaving us a review, I would be most grateful.
Today we are, we’re about to dive into a pretty extraordinary conversation. I think it’s one that you’re going to be really excited about, and I look forward to hearing about your experience and thoughts on the topic.
I am talking to Dr. Paul Turner, who is a professor of Ecology and Evolutionary Biology at Yale University and Dr. Benjamin Chan. He’s associate research scientist in Ecology and Evolutionary Biology, also at Yale. They’re right down the street from my mom, in fact, and not far from me here in Sandy Hook. Both are in Dr. Turner’s Lab, and their focus is on all things bacteriophage, so all things bacteriophage. If that’s a new term to you, you’re going to be Wikipedia-ing, it. Actually, I’m going to leave a lot of content…they’ve published a lot of papers. So you’ll have lots of directions, leads to follow in the show notes. If it’s a new term to you, I’m going to turn it over to Drs. Turner and Chan to just walk us through what the heck bacteriophage are, and why we’re extremely interested in them, particularly now.
Dr. Paul Turner: Thanks very much for having us on. This is Paul Turner. I can tell you very briefly you in the audience what a bacteriophage is. This is a virus, or we can think of them as any virus that is specific to infecting bacterial cells. We live in a very big, biodiverse world of viruses where essentially all organisms have one or certainly very many types of viruses that infect them, but bacteriophages are specific to only infecting bacteria.
Dr. Kara Fitzgerald: Okay, all right, that’s actually you answered in fact, my second question, that’s it, they’re limited to infecting bacteria.
Dr. Paul Turner: Yes, go ahead.
Dr. Kara Fitzgerald: Well, so why are you guys focusing so much attention on them? What’s, why are we thinking about bacteriophages? Well, why don’t we talk about … Yeah, look, we’ll go ahead, give me a little bit of background on what you guys are doing over there.
Dr. Paul Turner: Sure, I’ll give a little bit of a longer background, and even when I was starting my laboratory at Yale and then I’ll let Ben Chan go ahead and talk to you about what we’re doing lately. Essentially, I’ve been fascinated with microbes for my entire… what is it pushing 40? Almost 40-year career. The point is that bacteriophages are fascinating, because they are very biodiverse, like other viruses, they sometimes have only a handful of genes, and yet this is enough to make them very capable of infecting and killing bacteria. This has been of interest to people in just basic biology as well as biomedicine for a very, very long time predating antibiotics, and I’m sure we’ll get to that eventually.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: Essentially, I’m just emphasizing that I find viruses to be fascinating, and my group studies a lot of viruses including a lot of the species richness of phages on the planet, and lately for a very particular purpose, which I’m going to have Ben describe it to you.
Dr. Benjamin Chan: Sure. Lately, we’ve been focusing quite a bit of our effort on isolating and
characterizing bacteriophages that target particular pathogenic bacteria. Because antibiotic resistance is becoming quite a problem with rates increasing, and a very notable lack of alternatives to these antibiotics — not, very few new antibiotics or certainly no new classes of antibiotics coming out for a lot of the major gram-negative bacteria. So, phages are one approach that was tested maybe 100 years ago, and gained a little bit of popularity, which then disappeared, and now it’s being viewed again, as a potential strategy by which some of these infections can be managed. That’s where we’re focusing a lot of our time now.
Dr. Kara Fitzgerald: Yeah, okay. So, before we come forward to what you’re doing, what you referred to as pond to bench to bedside. It’s going to be fun to define that in a minute. First of all, there’s zillions of these bacteriophages everywhere, but they were historically discovered by a guy named is it D’herelle? He discovered, Felix D’herelle?
Dr. Benjamin Chan: Yeah.
Dr. Kara Fitzgerald: Who discovered the, in the early 1900s, and in there were … I mean, it was pretty remarkable what they were doing way back in the day, and what we were actually doing here in the United States for a period. Can you give some of the … Go through some of that original history?
Dr. Benjamin Chan: Sure, so they were…bacteriophages were discovered in about 1914 by this D’herelle guy and also another guy in England named Twort. This was before chemical antibiotics, for the most part, definitely, before the discovery of penicillin. With no real antimicrobials around to treat these infections, they were immediately recognized as a potential treatment. So, D’herelle and other started doing some really cool attempts at finding new phages, targeting these bugs and had some pretty, at least when you look at it, some pretty encouraging data suggesting that the phage therapy thing might have a real effect on infectious diseases. Then that interest sort of disappeared when these broad-spectrum chemical antibiotics were found.
Dr. Kara Fitzgerald: Right. Let me … Well, yes, so I just wanted to first of all, it’s interesting that, William Summer, released in 1999, a great biography of Felix D’herelle, and this book was one of the reasons why I’ve been bugging you guys for a while to … I really, really was looking forward to talking to you on this podcast, but a friend of mine introduced it to me in medical school years ago. I think it was in our microbiology class and of course we didn’t talk about bacteriophages in microbiology, but she on the side said, “Hey, you should read about these bacteriophages,” and she passed me D’herelle’s book and indeed, it was extraordinary.
Dr. Kara Fitzgerald: We were, we’ve been galloping into antibiotic resistance now for a while so particularly it struck me as incredibly interesting, but I felt rather powerless like what can we actually do? How can we have access to these? I’m going to ask you questions. I’m a naturopathic physician, so I’m into how we can, how I can optimize my own health and the health of my patients and eat a great diet. So, I’m going to circle back to you and pick your brain on how we might be, how we might cultivate if it’s possible at all, sort of healthy bacteriophage-ome if there’s such a thing. I’m going to circle back to those questions, but in the meantime, we’re thinking about D’herelle and at the turn of the century.
One of the things that I looked at when I was reviewing his book, again, is that they used phages for cholera and for typhus. I think you were talking about avian typhus in your paper. I mean, pretty extraordinary infections with good outcome.
Dr. Paul Turner: Yeah.
Dr. Kara Fitzgerald: Yeah, go ahead.
Dr. Paul Turner: Yeah, I think that it’s pretty amazing that both Twort and D’herelle realized that they had discovered some kind of a poison that would work against bacteria. Everybody, I guess, D’herelle is a French Canadian and Twort is as a Brit, and people are, they kind of take sides about who really discovered this, they are…
Dr. Kara Fitzgerald: Do they really?
Dr. Paul Turner: Yeah, my personal take on it and perhaps it has something to do with D’herelle having the only academic appointment in his career was at Yale for a few years. So I’m a little biased, but the point is, I think, Twort saw that I’m visualizing something here. It’s a poison against bacteria, but he kind of thought of it seemingly as merely a chemical poison. Whereas D’herelle had the insight to think, “Hey, you know, I can’t perhaps see this microbe, it’s too small for me to visualize with microscopy of my time, but I think it is an entity, I think it’s a biological entity.” Essentially, some people would say that D’herelle had it more correct when he found these phages. As you alluded to it, it became a very short interval between both of these individuals discovering phages, and then having the insight to say, “Hey wait a minute, why can’t this be used to attack a bacterial infection, and let me try this out?”
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: To be able to cure cholera in a chicken model, that is exactly what someone like D’herelle, this is what he did. It’s pretty amazing that decades before Fleming’s accidental discovery of antibiotics, penicillin, that essentially, these individuals, and those who followed in their path were onto something long before we discovered chemical antibiotics.
Dr. Kara Fitzgerald: Well, and they actually introduced later, so they started experimenting in
animals. And, that is probably when they begin to uncover that they, in fact, don’t infect humans, only bacteria. I get, I mean, they ended, over time, I guess you unfolded that they were really restricted to bacteria, or did D’herelle figure that out?
Dr. Paul Turner: Yeah, that’s a very good question actually. That takes a lot of insight, but it could be quickly gleaned that, I’ve got this mysterious thing that I’m calling a virus, and it is capable of infecting x and killing it being a bacterium, but it seems to be doing no harm at all, to the chicken itself, to a human who’s ingesting it. I wanted to say this, when you brought it up earlier about, we are essentially living in it and a huge ocean of viruses, especially bacteriophages on this planet, in the time that your listeners are going to be sitting wherever they are listening to this podcast. They’re inhaling dust particles just as they’re walking this planet and undoubtedly, those dust particles have viruses adhered to them, and the majority of them are going to be bacteriophages. They’re pretty much inescapable on this planet. You’ll see them in water, in the food you eat, especially if you like salads. So, they are everywhere, and the question is, what use could they be if humans wanted to harness them? And, you’re already touching on the fact that over 100 years ago, roughly 100 years ago, people were seeing the applications of phages and now that antibiotics are running out of effectiveness, it’s launching a whole lot of interest in phage biotechnology, what they could biomedically as well as another realm.
Dr. Kara Fitzgerald: Well, okay, so I’ve got a couple questions. I think we just turned the vo … So we were actually researching them in the United States, back in the turn of the 19th, the 20th century, is that right?
Dr. Paul Turner: That’s right.
Dr. Kara Fitzgerald: Then, okay, so then antibiotics kicked in which, interestingly, I think that you talk about this in one of your papers, they were aware, way back in the 40s, that antibiotic resistance was possible, but they still sort of nonetheless, dropped everything else and all hands on deck with antibiotics.
Dr. Kara Fitzgerald: When we were researching them here as I mentioned to you earlier, like Eli Lilly had an over-the-counter bacteriophage. Can you talk about that at all? I mean, what was the indication for that? Do you know?
Dr. Paul Turner: I don’t know that too deeply.
Dr. Kara Fitzgerald: It’s just so fascinating to me, like it was relatively evolved here for a short period of time.
Dr. Paul Turner: Yeah. I have to divulge that part of this re-surging interest in phages, it starts to reach back to all kinds of anecdotes, and you said this earlier, shame on your microbiology instructor for not covering phages, by the way.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: The fact that so much of this historical relevance is coming to light now, but even the people who are highly involved in the work like us it was a learning curve for us to figure out what had been done in the past and has been ignored, and maybe we’ll get around eventually to talking about the abundant work that has happened in places like former USSR countries, and Russia itself, and Poland. Look, a lot of that stuff is still not translated from those languages.
Dr. Kara Fitzgerald: Wow.
Dr. Paul Turner: Yeah, amazingly and I think there’s more of an earnest effort now to do it but it’s not that every last paper has been translated yet.
Dr. Kara Fitzgerald: It’s just this wealth of information, I guess. What I want to … So, just kind of thinking about this all, Eli Lilly having an over the counter, apparently, I mean, this is what I’m kind of finding as I’m surveying things in preparation for our conversation. They’re not, they’re pretty specific like one bacteriophage for one bacteria. I mean, is that basically true?
Dr. Benjamin Chan: Yeah, no, absolutely. It’s not even, it’s even more often more specific than that.
In that a particular phage can’t always infect all strains of a single species because they’re very, very specific.
Dr. Kara Fitzgerald: If, in fact, the Eli Lilly did have this product, it would be for extremely specific indication, like E coli, urinary tract infections or something.
Dr. Benjamin Chan: Yeah, and the way they got around the specificity, almost certainly Eli Lilly and definitely the Russian and Georgian groups that are still making these phage products is that they would take a bunch of phages that target these organisms and sort of pool them together into a phage cocktail.
Dr. Kara Fitzgerald: Okay, so then we dropped the ball here and put our focus on antibiotics and did a lot of amazing things. But, as we were doing that turning our attention elsewhere, as you pointed out, Paul, over in USSR, former USSR, they were just galloping ahead in this arena, and we have yet to uncover and understand all the work that they’ve done, and they’re still doing, right?
Dr. Paul Turner: Yes, and places like the Eliava Institute, which is in the country of Georgia,
they’re still doing a lot of great work there. It’s interesting how, historically, in some places the interest never faded. The fact that in Western medicine, it didn’t take off like a rocket that’s really been… you bring this to audiences in the USA like, “Wow, I’ve never heard of this before.”
Dr. Kara Fitzgerald: Yeah, that’s right.
Dr. Paul Turner: Because technologically we’d never invested in it. One side note to what you and Ben were just talking about. It is an amazingly biodiverse virus world, I’ve said that already. I have done some of my work in my career on what makes a virus more specialized, and what makes a virus more generalized. There are examples of viruses that are pretty general, and they will infect other species. We deal with this problem in human medicine with emerging viruses that could infect a chimp, or something that’s even more distantly related to a human, and then they can jump into a human.
Dr. Paul Turner: So, I’m only saying that there’s a lot of benefits to specificity. If you’re going to find a phage that’s going to target kind of set of genotypes of some pathogen, and those are the most important genotypes for say a urinary tract infection, then that’s awesome. That’s good specificity. I don’t know that people will never discover more broad host range viruses though including phages, I think that we still are at the tip of the iceberg with understanding how virus lifestyles work, what the range of them are. There could be very generalized phages that we just had not discovered yet, that’s my only point here. Because I think it may take a very, very long time to eventually stumble upon those, if there are very rare in the virus biosphere, but they could exist.
Dr. Kara Fitzgerald: Fascinating, and again the fact that we can use them as we enter into this
antibiotic resistance era, and also in this era of stealth infection, and the tick borne infections that can be really tough to treat and move into this chronic state. I mean, obviously interest in other tools that might be safer and more specific, even as you look for one that could have broader application. I just, it’s just very interesting and extraordinary to me. All right, so let’s … First, actually, I’m going to just for folks, again, who haven’t seen bacteriophages, they look like these little robots. I mean, they’re pretty extraordinary appearing, and we’ll put one on the show notes so you can go take a look. Any comments on that, on their appearance say relative to other viruses?
Dr. Paul Turner: Yeah, can I comment on that first?
Dr. Kara Fitzgerald: Yes, please.
Dr. Paul Turner: One of the things that has long impressed me is in this mostly microscopic world
of viruses, that you have a lot of differing morphologies. As you said, some of them look like these lunar landers where they’re complexity being that small is kind of amazing.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: In all honesty, some of them have a lot less impressive morphology. They’re very, very blah where they’re just rod like, so, iconically, a lot of people visualize bacteriophages by these lunar forms that you’re going to see but maybe listeners should know that, just as in viruses that infect humans and mammals, other mammals, plants, et cetera, you have a wide range of morphology, but there are these very compelling ones that look like miniature lunar landers that are, they’re pretty cool. Those are pretty distinct, yet common enough that they’ve become iconic for bacteriophages.
Dr. Kara Fitzgerald: Right. Let’s talk about some of what you’re doing. Let’s go, so you’ve come … How long, Paul, how long has Turner Lab been at Yale? I guess, since you started their back in early 2000.
Dr. Paul Turner: After a series of postdocs, but I’ve had my lab at Yale since 2001, so I’ve been here roughly 20 years.
Dr. Kara Fitzgerald: Right at just, you know, at the, you jumped into bacteriophage research at that time?
Dr. Paul Turner: Well, I was doing first bacteria research as a graduate student, with Rich Linsky, and then I moved into bacteriophage research with my first postdoc in 1995, and that was with Lin Chow, when he was at College Park, Maryland. He’s now at San Diego. It was really in about 1995 that I started working on phages, so a bit before I was over here.
Dr. Kara Fitzgerald: What were you doing specifically?
Dr. Paul Turner: Mostly what I was doing was using phages and other microbes, similar to how people sometimes used drosophila just as very rigorous and efficient and powerful systems to test biology questions. I was essentially doing that kind of work that would have perhaps some applied significance, but the kind of work we do now is much, much more applied. So, I’ve changed through my career. Whereas, Ben has been more on the applied side of, especially phage research for some time.
Dr. Kara Fitzgerald: Yeah. Okay, so then you, I guess, you were exposed to their wonderment, even back in the early 90s, mid 90s, you’re aware that they had the potential to be really precise killers of bacteria. So, then you moved at some point, obviously jumped over into applied, I mean, it’s just extraordinary. Talk about, talk to me about that, and we can … I mean, if there’s any kind of seminal tales that you have, from early, early on, do share or we can move right into some of the more current publications you have and experiences, but I just really want to hear about this pond to bedside journey.
Dr. Paul Turner: I’ll let Ben describe that. I’ll just say very briefly, that my early fascination when I started working with phages was that, at least in the laboratory, if you take a phage that is infecting some bacterium, it’s binding to it, this is the way that the phage recognizes that cell type and initiates an infection process. Along the way, as an evolutionary biologist, I came to appreciate, clearly, the bacteria, if they can, will try to escape that through their own evolution. They’re going to try to get away from this predator by changing to become less of a prey item.
Dr. Paul Turner: That’s a lot, that’s at the nexus of what we’re doing now, and at that time, in the mid-90s, I was looking at phage bacteria interactions and seeing how, wow, some of these changes that the bacteria undergo are so dramatic after you expose them to phages, that they either die, or you’re selecting for these mutants of bacteria, that have changed dramatically in their fitness, especially their ability to be pathogens. That kind of is one way of casting what we’re doing now, which I’m sure, Ben can describe. Sure, go for it.
Dr. Benjamin Chan: Wait, so you wanted to move into?
Dr. Kara Fitzgerald: Well, let me … Can I just ask a question about that, and then Ben, I want to just hear some of what you guys are just doing now. Some of the how you’re applying it. Paul, so were you seeing these bacteria become phage resistant?
Dr. Paul Turner: Yes.
Dr. Kara Fitzgerald: That’s a problem. That would be a problem potentially?
Dr. Paul Turner: No that’s…
Dr. Kara Fitzgerald: Yeah, go ahead.
Dr. Paul Turner: That’s a good question. If you’re going to use a phage to attack a bacterium, and it kills it, and you walk away from that very happy, then fine, you’ve done your job and the phage has done its job, but we can’t be that naïve. That can work up to a point, but then evolution kicks in and if there is some mutation that allows the bacteria to escape the phage, then that is what is going to be enriched in that bacterial population. My point here is that depending on the phage, and the target bacterium, if the phage is interacting with that bacterium by associating with something that is a structure, or a mechanism of those bacteria that make them pathogenic. Essentially just exposing them to the phage is going to kill them, but it will also cause their evolution to move generally, in a direction that’s good for medical treatment. It’s going to be pushing the bacteria to do something to become less pathogenic in a way to escape the phage, and I think that that has entirely to do with which phage you choose to use
Dr. Kara Fitzgerald: Got it, wow.
Dr. Paul Turner: That’s essentially, that’s the main idea that, Ben and I have been…
Dr. Kara Fitzgerald: That’s what you guys have been tussling with. On one hand, you’re killing it, but on the other hand, you’re actually wanting to induce mutations that would reduce the pathogenicity of that particular bacteria.
Dr. Paul Turner: That’s called an evolutionary trade off, and the world is full of them. Evolution solves problems, but evolution is not omniscient. You can solve a problem, proximately, but it might create a liability in your opportunity to do something else. I always give people the…now that people hear my talks often, they’re going to be tired of hearing this example. But humans are great apes that walk up right all the time, and that’s great, but it also gives us neck pain and lower back pain that I’m sure that chimps and gorillas don’t worry about.
Dr. Paul Turner: There are all kinds of ways that evolution can take you down a path that is improving your fitness, but it might make you more vulnerable to something else. So, if you take phages and you throw them at bacteria, they’ll solve that problem if they can get through evolution. If you pick the right phage, they’re going to solve that problem in a way you want.
Dr. Kara Fitzgerald: Yes. Wow. It’s ridiculously fascinating. I can see why you need to spend a lot of time on the bench before you jump.
Dr. Paul Turner: That’s why people like Ben are working like crazy in the lab, is that once we figured this out, I think that it’s, there’s a fair amount of optimism that you can find phages that will do this.
Dr. Kara Fitzgerald: Yeah
Dr. Paul Turner: It’s because he’s found them.
Dr. Kara Fitzgerald: That’s extraordinary. I think we’re always like, my instinct was to think it’s a bad thing. If we’re pushing the bacteria to mutate further, it can only lead to some horrible nefarious outcome, but in fact, you’re turning that entirely upside down. Well, can you talk to me… I, for instance, I just came up almost to the day, you guys released a really cool case report on looking at Pseudomonas Aeruginosa in a graft infection. I mean, and using phages there. I mean, can you talk to me about some of the applied phage work?
Dr. Benjamin Chan: Sure. Yeah, so we’re doing a bunch of applied work lately. In that particular case, we this gentleman had a long standing infection for many years that wasn’t resolving with standard antimicrobial therapy, and we had recently published on a phage that exploits one of these trade offs that, Paul was talking about, by either the bacteria would be phage sensitive, but resistant to antibiotics, or once it evolved resistance to the phage, it would be sensitive, to antibiotics. Considering that trade off as a potential mechanism we could exploit in treating Pseudomonas infections, at least, we deployed that phage, in addition to antibiotics to try, and treat his infection, and a single application seems to have done the trick, and we were able to clear that infection from him.
Dr. Benjamin Chan: Since that case, we have focused a lot on pulmonary infections, especially in cystic fibrosis, where we’re looking at also again at Pseudomonas Aeruginosa is a really common bug in those individuals. So, we have all these strains and people with these infections, and we’re basically going out into nature and the wastewater, everywhere collecting samples, and isolating new bacteriophages. Then we’re sort of characterizing them in the lab, so we know a bit more about the biology, and then we will find out what receptors are using to infect these bacteria, and then what the bacteria are doing in response to phage selection. Bacteria, and phages have been battling it out since they were bacteria, and so they’ve come up with ways to not die from phage infection, but they want to do this in the cheapest way possible, and often that just is manipulation of a surface expressed receptor or something.
Dr. Benjamin Chan: If we can select the phages, like Paul was saying, that utilized particular
receptors that are important in virulent, or antibiotic resistance, or albumin from the immune system, then we’re forcing them in to a trade-off where they either get killed by phage or they’re sensitive to antibiotics so they’re less likely to cause disease or tissue damage. I think that’s been really, so far, it looks like it’s been really successful approach of targeting these virulance factors. In Pseudomonas, at least and other bacteria has been really successful in treating these lung infections, and that we’re slowly able to manipulate the communities of bacteria in the lung to either be antibiotic sensitive or less virulent, and I think we’ve treated several cases now, and so far, we’re really encouraged by the outcomes.
Dr. Kara Fitzgerald: Extraordinary, so you found a single phage that will go after the Pseudomonas and it’s going to kill a bunch of them, but those that survive, since you’ve targeted the mechanism, the bacteriophage is using, to kill the bacteria. It’s a virulence factor, so it’s a receptor that increases virulence. I’m sorry, if my language around this isn’t quite right. Then those few that survive, are going to select, they survive, because they’re selecting for no longer having that particular virulence factor.
Dr. Benjamin Chan: Yeah, basically. I mean, so we have many different phages, but we’re using the ones that are targeting these virulence factors, because often the bacteria don’t need those virulence factors to survive. It’s, they’re just using it to like further infection or like damage tissue that helps them further infection, or sticking to tissue. Basically, if we can select for a population of, say Pseudomonas, they can’t do that, can no longer adhere to these epithelial cells or can no longer form biofilms, it would improve the status of the individual being treated and reduce the bacteria burden for sure.
Dr. Kara Fitzgerald: That’s awesome. So, the Pseudomonas, I mean, since it seems that it could actually remain there, but no longer be pathogenic?
Dr. Benjamin Chan: Yeah.
Dr. Kara Fitzgerald: So, it could actually continue to exist in the individual at the site, but it’s no longer causing an infection that’s significant. Would you say that’s true?
Dr. Benjamin Chan: It depends on the individual. In the case of cystic fibrosis, I think it would be really difficult to have a lung that’s ster … Well, in most people, but especially in CF, it’s difficult to sterilize the lung, I would say, and so if the community is going to be, if the lung is always going to have bacteria, I think our approach has been one that we should at least have a population of bacteria that’s antibiotic sensitive, and less likely to cause tissue damage.
Dr. Kara Fitzgerald: How…
Dr. Paul Turner: That’s how I like to think about it conceptually, too, because if you can’t
eradicate every last bacterium, then have the ones that are left over, be largely a virulent and therefore, they’re not really problematic from pathogenicity, and if they get out of control, if you’re sort of pushing them into antibiotic sensitivity anyway, then you’ll be able to, at least in theory, tackle it with the standard, traditional chemical antibiotics.
Dr. Kara Fitzgerald: Right, and I’m sure that’s happening in some cases, right? I mean, you talk about that in your writing where this would increase antibiotic response?
Dr. Paul Turner: Yes. I have to be honest; it’s working better than we thought it would.
Dr. Kara Fitzgerald: Is it?
Dr. Paul Turner: Because I think people, and I’m learning more and more about this all the time, the lung, has all these nooks and crannies and of course, but there’s a lot of in ecology you call this [inaudible 00:34:52], there’s lots of places to hide out. I think it’s an example of if you can go down an alternative therapy route, and get a good outcome, it actually then feeds back into more basic research about well why is that working so well? Then you start to learn more about your target problem, from the standpoint of, “Oh, I thought that, that would be more difficult.” Maybe it’s, I’m not saying and I have to be careful, I’m not saying that phage therapy is easy, or that it will work in all circumstances, but when you get consistently good outcomes, I think it tells you something more that you might research to get even better outcomes down the road. That’s the point.
Dr. Kara Fitzgerald: It’s just so fascinating. All right, so let me just ask a question. How rap … I mean, bacteria can mutate really rapidly, certainly not like human mutations, human evolution, so when might they? Like what kind of a time frame are we looking at with exposure to the bacteriophage? Are they going to mutate to no virulence?
Dr. Benjamin Chan: Well, I mean, I think if you maybe look at it less like a rate, and more … Well, I guess that could work, but more like a population. We find that maybe one in 100,000 to one in a million bacteria in a population would just be… will have a mutation present in one of these receptors. So that when the whole population is exposed to a phage, one in 100,000 survive, and those ones grow back up and fill up the population, right?
Dr. Kara Fitzgerald: Yeah.
Dr. Benjamin Chan: In the absence of antibiotics, an immune system or something, it’s quick like, and it’ll happen overnight if you’re growing them in a test tube. You quickly select for phage resistance. In a person, it can be a little bit different, just because most people have immune systems that are also acting on these bacteria, and often, they’re already on some sort of chemical antibiotic. So, if you just basically tilt the balance of this bacterial population, or you shift equilibrium a little bit, by adding a phage targeting a particular virulence factor, sometimes this can happen really quick, and then the infection can resolve because it’s now more sensitive to the immune system and antibiotics or whatever, but we see at least if you’re looking for hard data, we see like a pretty quick drop in bacteria density, at least in the pulmonary cases, we’re treating, in the sputum density of bacteria dropped two to three orders of magnitude within about three days.
Dr. Paul Turner: Yeah, so this is really consistent with what Ben is saying. That it’s a mutation that can happen in the bacterial population, it still is going to be relatively rare, and if you are using the phage approach, and you’re knocking the population down way to the point of only these survivors being there, then there could be a synergy with an antibiotic, like we talked about earlier, such that they’re either mutants that are escaping phage attack, but they’re sensitive to antibiotics, or maybe it’s a manageable enough bacterial load, that the immune system could be more effective, and helping to clear them out, assuming the immune system is working properly. It’s a numbers game, but it is, I agree with, Ben it’s kind of less about rates per se, because bacteria in humans do produce mutations at the same rate. It’s just that the bacteria are growing so much faster. In each generation, when they’re copying their DNA, that’s at the point that these mutants arise.
Dr. Paul Turner: So you have to consider it as, yeah, if you can get a handle in the laboratory, and the expected mutation rate, and the spectrum of mutations that should be in response to these phages that we use, then we can be much more accurate with predicting the exact numerical outcome, but the kind of trends, they make sense to me, as an evolutionary biologist, that this is what is happening in the system.
Dr. Kara Fitzgerald: Well, it seems like the turnaround time, to actually getting someone better is extraordinarily quick.
Dr. Paul Turner: It can be because it’s a completely different approach.
Dr. Kara Fitzgerald: All right, well, let me ask you some, I just want to back up because you said a lot there, and I just want to color in some of this. Going back to the first, this 2018, this March 2018 publication. Again, folks, I’ll link this on the show notes. This is from Evolution Medicine and Public Health. It was published actually, I thought it was published. It was published in March 2018. It’s phage treatment of an aortic graft infected with Pseudomonas Aeruginosa. In this one, how did you guys introduce the phages? What’s the root?
Dr. Benjamin Chan: Sure, so in this particular case, it was a rather complicated one, as maybe your listeners will see if they read the case. In summary, this guy had a dacron graft for an aortic arch replacement. Basically, it was infected with Pseudomonas at some point and so he had this infection for four years. Then actually, after a couple of years, and some debridements and standard treatment, he formed draining fistula, which was in the upper right, upper left quadrant that was draining Pseudomonas. Basically, that basically tracked all the way up to this little pocket near the base of this graft, base of the aorta, sorry. We initially had hoped to just directly access that collection of fluid with a needle, but it would start over by the time that we were trying to do this intervention. Basically, we applied it at the end of the draining fistula instead, and then so we just added a bunch of phage, plus ceftazidime and then basically just covered up that fistula. It seems like the phage might have tracked their way up there killing bacteria on the way.
Dr. Kara Fitzgerald: Yeah, they must have because it worked.
Dr. Benjamin Chan: Yeah.
Dr. Paul Turner: Assuming that there were bacteria throughout the fistula, then it would be like a predator, in a sense moving upstream towards where more of the prey are located, and that’s … I don’t, I’m not trying to be anthropomorphic about it, but I’m trying to let the listeners understand what’s happening here, is that, that’s literally what could occur. You have these cells being destroyed, and each cell that gets destroyed in the process, you’ve got hundreds of these new phages being created and being released, so you have this quickly amplifying drug of a sort, this phage and in the system, it quickly found more bacterial cells that were sensitive to infect the Pseudomonas Aeruginosa target cells and worked very effectively with one dose.
Dr. Kara Fitzgerald: Extraordinary. How did you guys get approval to do this?
Dr. Benjamin Chan: Sure, so we had permission from the FDA to use this phage in an emergency use, so they have a mechanism for emergency deployment of phages or other compounds if current standard of care, had not improve the situation, and obviously, the person being treated is informed and realizes it’s experimental medication. So we basically just went through that process and applied through the FDA to do this in an emergency case.
Dr. Kara Fitzgerald: Now, one of the things you talk about in the paper that I know is of big interest to our listeners, is the fact that, a major cause of antibiotic resistance is the development of biofilms. This particular phage that you chose, was active against the creation of biofilm in this case?
Dr. Benjamin Chan: Yes. Yeah, so we have a few phages in our library that can either break down or disrupt biofilms or can target some of the proteins or sugars or whatever necessary for bacteria to sort of attach to a surface and start producing biofilms and interfere with quorum sensing. We can manipulate each of these little switches to try and mess up biofilms.
Dr. Paul Turner: They’ve been seen in the literature, but not in all cases, have people worked out the mechanisms.
Dr. Kara Fitzgerald: Okay.
Dr. Paul Turner: To know why phages are better than antibiotics at permeating and kind of disrupting biofilm formation. Yeah, this stuff exists, but as Ben said, we’ve got lots of phages that show these properties.
Dr. Kara Fitzgerald: It’s extraordinary. I mean, I would say that antibiotics seemed to unfortunately work in or sort of promote in a biofilm formation because the bacteria want to survive.
Dr. Paul Turner: Yeah, pretty much biofilms are generally impervious to antibiotics, so that I would agree that the presence of antibiotics would therefore select for bacteria that more resistant to them. Yeah, it’s not helping. I think I can easily say that with confidence, it’s not helping the process, whereas something like phages and using them should take us to a better state.
Dr. Kara Fitzgerald: Yeah, which is why this man had this infection for four years and wasn’t
responding to standard of care, really, at all, and the morbidity and mortality of these graft infections, the rates are high.
Dr. Paul Turner: Yeah, there a lot now. Again, I’m learning along the way with this. There’s a lot of surgeries that are rather routine, and they involve these artificial substrates going in the human body, felt and dacron and polypropylene, and that’s great. I want my surgeon to be able to work on me very reliably and effectively so that I’m not going to be harmed during the process of a routine surgery. The unfortunate consequence is that this artificial stuff in the human body seems to be particularly good substrate for some bacteria to form biofilms.
Dr. Kara Fitzgerald: Yeah.
Dr. Paul Turner: And some are pathogenic, and if you have antibiotic resistance, increasing in those pathogens, and that’s a collision course to on the one hand, the surgery becoming easier, but the stuff that might colonize that surface is becoming harder to treat. That’s not good news, right? You’re sort of these two trains are running towards each other on a track, and better to do something to prevent that.
Dr. Kara Fitzgerald: Where did you find the phage for this case? I mean, were you out hunting
around, were you at the Potomac River here are the Housatonic or the myriad ponds that dot the New Haven county where you are? I mean, or did you have it in the lab? I mean, where, how did you figure it out?
Dr. Benjamin Chan: That phage came from a water sample that came from a dodge pond, which is in Lyme or East Lyme.
Dr. Paul Turner: It’s near East Lyme.
Dr. Benjamin Chan: East Lyme, Connecticut. Yeah, so we have, I mean, we have water from many of the ponds around here.
Dr. Paul Turner: Now, some of it, I think, at that time, I should say, there are all kinds of
interesting lab groups right down the hall from us and one of them, David Post’s group, they were doing aquatic ecology work, in that pond, they study some of the fishes that live in that pond. We essentially capitalized on…some water samples were literally coming to our doorstep, because colleagues in our department, were bringing them into the building.
At that time, Ben is just searching widely for interesting phages. It turned out that, that one pond near East Lyme, Connecticut, it’s either East Lyme or Old Lyme, I can’t remember which but the point is that it’s a, it was a hit, it was a good hit, in terms of defining that phage, and so you never know what you’re going to find.
Dr. Kara Fitzgerald: Ben, you were working, you knew this case existed. They reached out to you and you were on the hunt for the appropriate phage.
Dr. Benjamin Chan: Yeah, so we … I mean, we had actually this phage, we just didn’t quite know the
properties of it at the time that the case would have appeared. Yeah, so we had this and then of course, we’re always, always, always collecting more and more and more phages. I used this strain from this individual and we tested this phage and found that it had this cool, cool trade off. Then, of course, we did a bunch of lab experiments to verify it, and to sort of simulate this treatment. Yeah, it’s basically just, it’s constantly a hunt. So we get sent strains from all over the world for people of all different directions, and we’re just always looking for more strains to try and help out.
Dr. Kara Fitzgerald: It’s amazing, I would imagine you’re busy. I’m sure people are listening and either the physicians listening want to refer to you, or there’s individuals listening who’ve got some sort of chronic infection, and are … How do you, do people call you up? Is it a possibility to refer to you? I mean how would one access phage therapy?
Dr. Benjamin Chan: No, absolutely. I mean, obviously, it might not be for everyone, and it’s purely an experimental treatment, and they would have to go through the right procedures to make sure that we get permission, and the current therapy has been tried and failed. As we’re starting to build this approach into trials here, but people can call me. My number is on the website that I sent you. They can email me, they can hit me up on Instagram or whatever.
Dr. Kara Fitzgerald: Okay.
Dr. Benjamin Chan: I’m pretty easy to get ahold of.
Dr. Kara Fitzgerald: Awesome. That’s perfect. Okay, so we’ll list all of that in the show notes. I’ve got some more questions for you. I want, so going back to cystic fibrosis, how are you introducing the phages there?
Dr. Benjamin Chan: Currently we’re treating via nebulizer.
Dr. Kara Fitzgerald: Okay, that’s what I was thinking. Yeah, cool. Okay, yeah go ahead.
Dr. Benjamin Chan: Basically, we selected that, because we wanted to get the most phages to the site.
Dr. Kara Fitzgerald: Yes.
Dr. Benjamin Chan: I think it makes sense. Also, because people obviously, with CF, are used to nebulizing and so it just sort of integrated well with their current treatments.
Dr. Kara Fitzgerald: They, and you only need to sort of … Is it a single application?
Dr. Benjamin Chan: We’re treating for once a day for a week is what we’re trying to do now.
Dr. Kara Fitzgerald: It’s amazing. Now, one of the things that we’re thinking about a lot in our world, of course, is the predominant microbiome, and there is a microbiome, I don’t know a whole lot about it, but there was a microbiome present in the lung. There’s a concept that we think about in our world called colonization, resistance, where we want some of the, we want the good guys to outnumber and the bad guys and just maintain some ecology balance and be, we want the host to sort of be hospitable so there’s a nice, happy ecosystem, and we keep pathogens at bay that way. Do you think about that, in this context, like, supporting the predominant microbiome?
Dr. Benjamin Chan: Yeah, no, definitely. I mean, lungs are a little bit more, I think, complicated, but we definitely keep that in mind, which is, I think why we’re targeting virulence factors. We’re only targeting the stuff that have these bad proteins or sugars or whatever.
Dr. Kara Fitzgerald: Yeah.
Dr. Benjamin Chan: Selecting for that environment anyway, because this good microbiome is also especially good at out competing invaders. If you’ve already got this healthy microbiome you can prevent some of the pathogenic bugs from colonizing. Definitely, we try to keep that in mind when we’re developing these treatments.
Dr. Kara Fitzgerald: That’s amazing. Again, it’s just really neat. So you’re killing the bad actors, but it’s not broad spectrum, again, so the good microbiome is there surviving and thriving. Do we, I mean, if you were to take DNA analysis, stool analysis using PCR, some technology is kind of becoming bigger and our space. I mean, are there a lot of bacteriophages as part of the GI microbiome in humans? I mean…
Dr. Paul Turner: Yes. Yeah, and the thing is that they have had less attention, but they are
certainly there. The role they play, if you’re talking about a multi species community, pretty much any microbiome, you’ve got more than one species of bacteria there. You may not have very, very, many depending on the site of the body. The point is what phages are there all the time, some of the time? What role might they have in regulating the relative numbers of the cells within each of those species in that community? This stuff is still largely in its infancy. There is some terrific work going on. I just, I don’t think it’s a stretch for me to say that the residence of the microbiome that have received the most attention are the bacteria.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: When people are doing active work on fungi, viruses, bacteriophages, archea, I mean, it’s happened, but I think the beauty that we’re going to see in the next few years, I don’t know how quickly we’ll get enough information from enough locations in the human body to say that we have some confidence in what is a typical microbiome? That’s really the problem, is there a typical microbiome, right?
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: People eat different foods, they have different genetics, and all this stuff can easily play into it. So that’s where I know a lot of terrific people doing microbiome work and at least the ones who I know well, and do the fabulous work, they understand that this is a very complex issue. It’s not like, “Oh, yeah, here is the standard microbiome for this man, in this location of the body as a man and, or a woman.” They’re all the same and it’s very … It’s still a lot of work to be done, but what you alluded to is true. Ideally, we’ll get to some point where we have a lot of trust in the ability of a phage or phages to come in and prune out a bad actor from a microbiome. I think we’re already kind of there, because it’s working. Now, how consistently it will work from person to person, we’re finding that along the way in clinical trials, and so it’s a very exciting time, but there’s a lot of new research, new discoveries to be made.
Dr. Kara Fitzgerald: Yeah, that’s right. It’s just extraordinary. It’s an exciting time for our world to where we’re kind of early adopters of some of this new higher throughput, omics technology, in my fields, but I know just changing the specimen, just like or taking, using a stool specimen may not be the best way to actually analyze the microbiome. Actually, there’s all sorts of eco niches, so wherever you look, you’re going to see wildly different, I think, complement of organisms. So, bacteriophage probably outnumber bacteria, do you think, in the human GI tract?
Dr. Benjamin Chan: Definitely.
Dr. Paul Turner: Yeah, it is.
Dr. Benjamin Chan: It’s 10 to one everywhere.
Dr. Paul Turner: Yeah.
Dr. Kara Fitzgerald: Okay.
Dr. Paul Turner: And they are much smaller; it’s easy to outnumber bacteria if you’re only a very small fraction of their size.
Dr. Kara Fitzgerald: Yes, right. Well, I would imagine, I mean, as research moves forward we’ll just know better what an integral role they’re playing in homeostasis and health. Would you say that’s true?
Dr. Paul Turner: Yeah, I think we’ll get more and more knowledge, because we’re trying. The real trick is especially what you just said about homeostasis. It’s easier to study aberrant phenomenon than it is to say, “Oh, now I’ve got a handle on what is homeostasis and what is-” To me, of course, I’m not an MD, I should make sure your listeners know that, but that’s what fascinates me about medicine, is of course, you turn a lot of attention to when things aren’t going well, that almost by definition causes us to sit back and rest on our laurels about when things are going well. It’s not that easy to get a handle on what is the microbiome doing under the most benign and useful circumstances, and I hope that that research goes as quickly. I think I have to express my pessimism. Disease hurts, morbidity, mortality, it gets more attention, because it has to.
Dr. Kara Fitzgerald: Yeah.
Dr. Paul Turner: Ideally, we’re going to see a big push in microbiology and microbiome research, and phage research, et cetera, for the basic research of healthy microbiome. I know it’s happening, but I just assume that more attention is going to the disease state than the aberrant state.
Dr. Kara Fitzgerald: Right, right. Well, and that kind of answers, at least somewhat my next
question. I mean, we’re all, everybody’s eating their fermented foods, or taking probiotics, they’re everywhere. If we think about wanting to nourish a healthy microbiome, I mean as far as our virome, our phages go, there’s not really at this point, you would say, there’s really not a hell of a lot of research on how we’re going to do that other than probably, it is not dissimilar from taking care of our, a good bacteria in our gut. I mean, I would imagine eating a good whole foods diet, and the myriad things we know, that keeps elimination normal and sufficient fiber and so forth. Those things are probably favorably influencing phages.
Dr. Paul Turner: Now, however.
Dr. Kara Fitzgerald: Yeah, okay.
Dr. Paul Turner: It is important to think about, imagine you’ve got a healthy microbiome, and it’s an all the right balance of equilibrium, of species that are present there, and you happen to eat, I don’t know, a salad one day that has some phage on it, that goes into your gastrointestinal system, sometimes you can make it through to the site where it would affect this microbiome by pruning something out that should be there, right?
Dr. Kara Fitzgerald: Yeah.
Dr. Paul Turner: I mean, that’s possible, and the question is whether that’s already happening in IBD, inflammatory bowel syndrome or something. What is it when people see an overabundance of some phages associated with IBD? Is that because they’ve chased out something that should be there or what is going on? I think that from the standpoint of phages entering into systems and disrupting them to mess up equilibrium, I have to be fair, in saying that, that’s a possibility too.
Dr. Kara Fitzgerald: A possibility, okay. Yeah, well then on that question, I know, we’ve got to wrap up here, but I just have so many questions. Are there contraindications for phage therapy?
Dr. Benjamin Chan: Not really. They should not impact negatively any of the current antimicrobials that are out there, and as far as we can tell, they can be used with anything, but we still are looking at that and need to figure it out more. But, at this point, we don’t see any reason that there should be any.
Dr. Kara Fitzgerald: Okay, and any side effects?
Dr. Benjamin Chan: None. None that we’ve observed with clean preps of phages. They’ve perfectly safe as far as we can tell.
Dr. Paul Turner: Yeah, what people have to be careful of is, this is what Ben’s alluding to, if you prep phages for use in humans, you have to make sure that in your prep, it doesn’t have some toxins that were present, that were in the cells that were destroyed as you made the phages.
Dr. Kara Fitzgerald: Right.
Dr. Paul Turner: They would be there, and you would be delivering them by mistake to a patient, and perhaps bring them harm. You have to be careful that that prep is clean and so those who are doing this work carefully, are super attentive to that, and my hope is that everybody’s doing it carefully.
Dr. Kara Fitzgerald: Right, right, right. So, that could be a compromised sample, it could be a huge problem. Especially if you’re introducing it into somebody who’s really vulnerable. What are you guys, so let me just, what about some of these, like people who move into sort of chronic Lyme are some of the co-infections in tick borne co-infections that can be really hellacious these days. Have you used phage therapy in these populations at all?
Dr. Paul Turner: No.
Dr. Benjamin Chan: I think a lot of those bugs are we don’t want those necessarily, but the phages definitely exist for borellia and a lot of these tick borne bacteria. Maybe there’s a future there for phages. Yeah, I don’t know.
Dr. Paul Turner: Yeah, I think that what you’re speaking to, is that there is a lot of optimism based on this recent success that we’ve had, and others. That you pick a favorite target, you use this approach, and maybe you can get somewhere.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: I think that that is a reason for optimism. What we’ve learned is that it is hard to go after all these targets. I love speaking about this research, I’m sure, Ben, same thing, and inevitably, any talk I give, especially if it’s to an MD, they’re going to just raise their hand and talk about their favorite problem.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: That’s awesome. It means I got them excited about this potential, but this is where we should be educating people to do more of this work in a useful way, and spreading that wave outward. Get … Because we cannot do it all. We’d love to do it all, but we can’t do it all. Yet, I do stand by the fact that phage bacteria work is not super, super expensive. We teach courses to undergraduates that get them involved in this work by literally learning the tools in the classroom, as first year students with no prior research experience. This is very effective as a gateway to doing independent research in the United States, especially through a course that was developed at University of Pittsburgh, by Graham Hatfull and then it has spread throughout the United States.
Dr. Paul Turner: I literally think that there’s like a new generation of scientists right now in the USA, that have cut their teeth on research, by exploring phages, and you’re going to hear more and more about this in the coming years. So, what is my point here? Is that the wave outward, I think, is already happening. You have young people who are doing this work. They’re seeing the work that, Ben and I and others do, and they’re like, “Oh, wow, not only did I learn this in that super cool lab course, but those individuals at Yale and elsewhere, they’re actually doing this, to try emergency treatment in patients and kickstart clinical trials.” I will tell you it’s not that the techniques that they learned in the classroom are not that different at all from what we’re doing, and I see a lot of a potential for young people to get involved in this and for scientists of the future to do this work.
Dr. Kara Fitzgerald: You can, once you identify them in the lab, like let’s go back to the graft case with Pseudomonas, you can then just maintain that sort of a little colony of those bacteria phages specific for that Pseudomonas Aeruginosa?
Dr. Benjamin Chan: Yeah, I mean, we basically just have hundreds of phages just sitting in the fridge. They’re pretty stable, and they just sit in liquid until we need them.
Dr. Kara Fitzgerald: Okay.
Dr. Paul Turner: You can keep them in the fridge, you can keep in the freezer, there’s a way of freeze-drying phages, setting them on a shelf. I think there’s a lot of potential in places that don’t have a lot of refrigeration, or even electricity that you might be able to keep these. That’s happening, just to be clear, you can go to places and they’ve got these freeze-dried forms of phages for you to purchase in a pharmacy without a prescription, but that’s for a different day.
Dr. Kara Fitzgerald: Right, right, right. It seems like for biggest, for efficacy, you’ve got to deliver it to the side of infection. I know that phages are you can purchase OTC phages now in this country in a probiotic combination. I’m curious, do you have any thoughts on those? Have you thought about that at all? If you’re trying? Yeah, go ahead. Go ahead, Ben.
Dr. Benjamin Chan: I haven’t thought much about them. I mean, I’ve seen them and I guess I’ve heard people have bought them, but I don’t know much about them.
Dr. Kara Fitzgerald: Okay.
Dr. Paul Turner: Is your question… is not about delivery?
Dr. Kara Fitzgerald: Well, I guess it kind of was I sandwiched two things together. You so far in the two cases that you’ve discussed, you had to really deliver them right to the site. The lungs, you nebulized it, but if you’re taking … So, there’s I know that there’s e. coli specific phages available in probiotics, but if you’re actually using it to treat a UTI, and you take it orally in a probiotic capsule, I’m guessing that, that might not actually, that the phages might not reach the urinary tract.
Dr. Paul Turner: I think, actually, you’re highlighting a very core interesting thing that’s going on in phage biotechnology right now. If you want to use phages for a particular purpose, how do you deliver them? If you’re targeting the lung, if you’re targeting the intestine, you’re targeting whatever, what’s the best way of getting them there? I think, frankly, there might be multiple routes.
Dr. Kara Fitzgerald: Okay.
Dr. Paul Turner: If it’s just brute force intravenous, I don’t know that that’s always going to be a good idea.
Dr. Kara Fitzgerald: You’re right.
Dr. Paul Turner: Lots of ways that people are thinking of doing this, but you’re hitting on the core thing, is that it deserves greater attention and research, because of course, you want to deliver it in the easiest way possible,
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: The best way, you need to figure it out.
Dr. Kara Fitzgerald: One more comment, this is way too long, but it’s so interesting. One more comment. As I was thinking, as I was preparing to chat with you guys, I was thinking about these autoimmune, these microbial triggered autoimmune diseases. The one that came to my mind that, I think there’s some decent science around is rheumatoid arthritis, where we know P. gingivalis of the oral micro pathogen in the oral microbiome can actually trigger rheumatoid arthritis and the production of anti CCP antibodies, which are they’re fundamental to it. Also, Proteus Mirabilis, which can exist in the urinary tract can trigger RA and susceptible in production of auto-antibodies, in susceptible individuals. It just seemed extraordinary to me, that one might be able to turn off RA potentially, with using phage therapy against these two bacteria.
Dr. Paul Turner: Yeah, I think you’re seizing on exactly what the promise of phage therapy could be.
Dr. Kara Fitzgerald: Yeah.
Dr. Paul Turner: If you know enough from research that tells you the presence of something in the oral microbial community sets you for a higher risk of something that may be a decade in the future.
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: Whether you can prune it out now against the future, I mean, I think that, that is cool, right?
Dr. Kara Fitzgerald: Yes.
Dr. Paul Turner: If you think about that, that we’re in its infancy to know whether that could be effectively done in just any old person.
Dr. Kara Fitzgerald: Right. It will have to be somebody who’s genetically susceptible to … Yeah, and then you’d have to identify that as initially, but I mean, that yeah, it’s just very interesting. Well, thank you so much for joining me today in New Frontiers, it’s just been fabulous talking to the both of you. I appreciate your work and look forward to just seeing what unfolds over there at Turner Lab.
Dr. Paul Turner: Thank you it was a pleasure. Thank you for having us on.
Dr. Benjamin Chan: Yeah, thanks for having us.
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