Baylor College of Medicine

Phage Therapy in the 21st Century




[Intro melody into roundtable discussion.]

Juan Carlos: And here we are this is the Baylor College of Medicine resonance podcast. I am your host Juan Carlos Ramirez.

Sabrina Green: And I'm Sabrina Green.

Juan Carlos: And Sabrina is the head writer of this episode. And today we're going to be discussing phage therapy in the 21st century featuring Drs. Anthony Maresso and Barbara Trautner. But before we interview them we want to give you a little a little background. Sabrina would you mind kind of sharing what our phages anyway?

Sabrina Green: Sure! This is my favorite topic so phages or shortened for bacteriophages are viruses, but don't let that keep you from don't let that put a bad image in your mind because these viruses only infect bacteria. They don't infect human cells. And they're the most abundant biological entity on the planet and you'll hear in the interview a little bit more about phages. But right now just giving you a basic overview. There's estimated to be 10^31 phages on the planet. So this is more than anything, like if you combine bacteria human cells everything it's still not as much as there are phages on the planet.

Juan Carlos: And it's like what like Avogadro's number? When we think of viruses or bacteria phages and we always think like terrible things, especially right now, right? So this recording is taking place at the time of the coronavirus, right. So when we think of viruses we think of, you know, catastrophe and illness and but very rarely do we think about them being used as like treatments or in clinical setting.

Sabrina Green: Right and that’s why I think sometimes they can get a bad name. But these viruses have been studied since the 1900s and there have been no instances of phages ever infecting a human cell. So they're completely bacteria infecting viruses and they've actually when they were first discovered they were used for phage therapy. So phage therapy is
using these viruses to treat infections in humans or animals.And this actually predated antibiotic. So antibiotics the discovery of penicillin was in the 20s and so phages were actually being used in the US and in other countries before even antibiotics were discovered and continue to be used in the Republic of Georgia at the Eliava Institute. So here in the US they actually aren't they are not FDA approved for clinical use but they are used in agriculture and they're considered GRAS or generally regarded as safe. So very safe, but still we still need clinical trials in order to get them FDA approved for clinical use

Juan Carlos: I wonder what it takes to get them approved? I think its got to be like a lot of fear. and you know now I think we're just very scared of them.

Sabrina Green: If phage were just discovered today I think it would be a lot easier but because and it's funny though because we have so much research so much data out there about phages with the history of it still kind of makes it harder for it. I believe this is my opinion, for it to be approved for clinical use but like I said, if you were to discover it today, I feel like people would be just amazed and excited and we would start clinical trials right away.But in the U.S. It's still considered experimental. There are centers though that you can get phage therapy. Like if you have an antibiotic-resistant infection and you've taken antibiotics and there's really no drug that seems to be working you can get experimental approval for phage use and that is how these centers are actually getting patients to be treated with phage.

Juan Carlos: Cool. Well, I mean I'm pretty new to all use the use of bacteriophage in these clinical trials and to treat people with resistant bacteria. I'm hoping to really learn a lot more today through Drs. Maresso and Dr. Trautner!

Sabrina Green: So that's the history. So what are we doing now with phage at Baylor College of Medicine? So we have TAILOR or tailored antimicrobials and innovated Laboratories for phage research. This is a service center at Baylor College of Medicine that's developing phages suitable for clinical use to help treat these vulnerable patients that get these antibiotic-resistant infections that nothing else can treat. They're also providing phage for other uses too in agriculture for instance. So joining us today will be Dr. Anthony Maresso. He is an associate professor at Baylor College of Medicine and he came from he got his PhD from the Medical College of Wisconsin, and then he got his postdoc at the University of Chicago in 2008 and shortly after he joined Baylor College of Medicine has been working in bacterial pathogenesis mostly but recently has been working with phage. So treatments for antibiotic-resistant infections using phage.

Juan Carlos: And we'll also be joined by Dr. Barbara Trautner who received her Bachelor of Arts from Princeton University her MD from the University of Virginia medical center, and she is currently a clinician at the VA Michael DeBakey Medical Center. She is a professor of Health Sciences services and research she is also a professor and director of the clinical and Health Services Research and she's board certified in Internal Medicine and comes very highly decorated with numerous awards and it's a pleasure to have them both here. So without further ado, let's get into the episode.

[Intro melody into episode.]

Juan Carlos: Welcome.

Anthony Maresso:  Thank you for having us.

Sabrina Green: Can you both tell us about yourselves and how you got interested in science medicine and research?

Maresso: Barbara you can go first.

Barbara Trautner: OK, I’m Barbara Trautner I’m an infectious diseases physician in the clinical practice at the Houston VA. I became really interested in research really late. Along the ways when I was an infection diseases fellow. And I was required to do a year of research. But I found the research was so directly relevant to improving my patients care. That really touched off a love of research that eventually inspired me to apply for career development award in the NIH followed by one from the VA and eventually completing a PhD in clinical investigation.

Anthony Maresso: My interest in science started when I was actually very, very young perhaps three or four years old. I recall being fascinated by the natural world in particular animals and reptiles and my father used to take me fishing my mother too at times and when I when I recall was maybe being four years old and catching a fish and just remarking at how slimy it was and wondering why it was that way. Why did it need to be slimy to be in water? And I don't think I've ever sort of wavered in my interests since then. I knew that I wanted to do something that would allow me to interrogate the natural world and so science was a way for me to do that. The interest in medicine. That is applying science to the benefit of alleviating disease in humanity occurred somewhat later. I wanted to be for the longest time a veterinarian, but then I worked in the veterinary clinic and I found that that was something that wouldn't allow me to dig deeper into real problems and then my mother got sick. She was diagnosed with lupus.

And when I recall from that was that she had really no ability to explain what was happening to her and neither did her treating physicians and that's when I sort of realized that I could use my interest in science to try to enhance levels of knowledge for things like this. Research is just a natural extension of that. So everything fell in line from that point forward.

Sabrina Green: Thank you very much for answering that how did you and I'll start with Anthony first get involved with phage research? And what do you find most interesting about phages or phage therapy?

Anthony Maresso: So to be to be honest, I've been I've been interested in phage ever since I was a postdoc at the University of Chicago, but sometimes when you get into research you are you have to sort of work on what the environment that you're in you have to kind of work within the confines of that environment. And so I've always had my eye on kind of the properties of phage because they're so such fascinating little, little creatures, but I had to be practical in being able to do the science in the particular lab I was in. So I've always had an interest in it from that point forward, but I came into it more concretely when my colleague here, Dr. Trautner and another colleague of ours a virologist Dr. Ramig sent to me a proposal that they wanted to submit to I believe it was the NIH and in that proposal they described how they were gearing up to use phage which are viruses that attack bacteria and they're very good at killing bacteria as a possible treatment for infections with a bacterium called Pseudomonas aeruginosa, which is particularly troubling for those that have Cystic Fibrosis and are badly burned. This organism can exist in those environments and infects those wounds. And I knew that at that point that this was the sort of an opportunity to finally get involved with my laboratory in this field of research because I had some extra seed money that the college had given me to do that.

And so it was just more or less an opportunity. An interest early on but not being able to take advantage of the opportunity until presented to me and Dr. Trautner and Ramig with an initial grant seeking my expertise really in bacteriology, which is my primary field of interest allowed me to then enter the field and it's been wonderful since then.

With respect to phage therapy goes back to the to what I started with when I talked about how I got interested in science, which is phages are are this, perhaps the world's greatest predator of bacteria. Antibiotics are often what people think of as killing bacteria, but phage have been co-evolving with bacteria and learning how to infect their cells for nearly two billion years. And so they've in essence perfected this process and so if one thinks sort of outside the box a little bit one realizes that phage can be potentially used is a way to control bacterial populations. And to clear bacterial infections even but the real the real benefit of phage unlike sort of chemical antibiotics, which do not have the ability to change in real-time. Their chemical structure is fixed in space and time. Phage are not bound by that limitation because the basis of their change is mutations in their nucleic acid, and they will acquire mutations with time just in their normal replicate of cycles and some of these mutations can be used to our advantage to improve the ability of a phage to target a particular bacterium and actually makes it make it more efficient at killing. And so the real difference here is that phage can be evolved in real time and adapted in real time to confront bacteria in real time. And it is this advantage that bacteria have used against us the fact that they adapt so quickly to our antibiotics become resistant to them and render them inefficient. But phage can be changed in about the same amount of time bacteria can and I think it's sort of incumbent upon us to explore the science of whether that can be used to develop antimicrobials to bacterial to treat bacterial infections in patients were antibiotics of sort of not been able to help them.

Sabrina: Dr. Trautner. Do you want me to repeat the question?

Barbara Trautner: Phage research has a little bit of a serendipity in it and maybe also a message to our students about how to prepare to go to scientific conferences because there's no science to preparing to go to a scientific conference so that get the most out of it. I was working with probiotics a benign E. coli as a way to ideally prevent urinary catheter colonization in persons with spinal cord injury and thus prevent symptomatic catheter-associated urinary tract infection. But I got really nervous what we're good probiotic because it was a weakened strain of E. coli, but I thought it could make people sick in the right setting. So then I said look at colicins which are antimicrobial product secreted by the E. coli that can kill other strains of E. coli because of the colicins are really just parts of phage that have entered into E. coli genome and that it makes these phage parts that kill other strains of E. coli.

Well, so it's pretty easy for me to get from there. Wouldn’t it be really cool to work with phage as a way to kill the resistant bacteria in people’s bladders that are causing UTI? And  then I looked up phage I didn't have a background in anything related to phage. I look them up on the web and I couldn't believe how cool they looked like they were the coolest looking little animals. And Anthony said he wanted to start out as being a veterinarian. Actually I did too until I realized animals couldn't talk to me and then I switched my sights to being a doctor.

Phage are the most amazing cool animals and kind of like the bacteria. I feel like they could all be my pets just like all the bacteria that I worked with. So the way I really got in the phage research though is why you have to prepare for scientific meeting. So I was going to a meeting on device-related infections and I think I had some little piece to present but I was clearly the junior person among the presenters. So I looked up every other presenter and their last two papers and one of the people so I could have conversations with them about their work. It was a small conference room about 25 speakers. So one of the people I looked up have been doing studies with trying to prevent urinary catheter colonization by the pseudomonas just like I was studying that he was using bacteriophage for it. And so we struck up a conversation. He worked at the CDC eventually I sent my research the technician from my lab to his lab learn how to work with phage and it was all because I had read his papers before I went to the conference and heard him speak.

Sabrina Green: Cool. I didn't know that story. Thank you!

Barbara Trautner: Yeah, I can shoot original papers by Rodney Donlan. He's at the CDC and the first author is Fu and it was a bacteriophage cocktail to deal with pseudomonas colonization of urinary catheters. I just couldn't believe how relevant it was to my own work. They were working with the same silicone type catheters. They were using real urine. They had encountered a lot of the problems I had encountered and so we really had a great conversation that took off from there.

Sabrina Green: So actually phage therapy has been used before and it's still used in other countries. Why do you think it is not in use in the US but still widely used in Eastern Europe and are there actual roadblocks to getting phages approved for use in the US and what do you think these roadblocks are? I'll start with you, Dr. Trautner.

Barbara Trautner: Yeah, people don't trust it. And I think it's because not only did it come from Eastern Europe, but until very recently they were not good clinical trials and there were a lot of people a lot of the phage studies are a little bit like some of those overly zealous case series you see of weird things like vitamins or something. That just doesn't end up working. To be specific, I got a email from someone wants help with their mother who's got a just organism in a wound and they're looking for help with treatment and I said we would be glad to help but I really need to talk to your treating physician first her treating physician first so I can look at the situation see is that, you know amenable to phage work. I gave my cell phone number and asked the doctor to give me a call. I haven't heard a thing. I mean, they're just suspicious of phage. They won't give me a call. I try to reach out to them. I think cause they're alive. I think people don't know what it is. And there's a lot of quackery out there that gets mislabeled as appropriate medical care and I think phage are getting lumped in that group, unfortunately.

Sabrina Green: So you think a lot of doctors feel that way or just the general public?

Barbara Trautner: Oh, no, I think it's doctors. I don't think the problem is with the general public. I mean, you know you have those are the radio and they managed to convince the general public that all sorts of things are good for your health. I think its doctors and the suspicion of a living organism. I think people hear experimental and they think I don’t have time to mess with that. I don’t want to do that. And I get that. I mean I'm a practicing clinician. It's so hard to find time in your day to do anything even slightly different because you're very overwhelmed with what it is. You got to get done that day. So we need to make it really easy for practicing clinicians to access phage therapy that is experimental with us doing the work for them.

Sabrina Green: Okay. Anthony.

Anthony Maresso: Yeah, I would agree with Barbara and what she said, but I would also add that. I think there are two other major driving factors that have sort of suppressed phage science and phage therapy and in America. Not directly suppress. This is just a sort of an indirect product of just what happened. The first is history. So phages  were discovered in the late about 1917, 1919 by two scientists and they described this unique activity where they could see a clearing of bacteria on a plate with some bacterial extracts and drop of water and they wondered there is something in this that's killing these bacteria and so it wasn't really realized till much later about 20 years later these actually viruses that do this, but we now know that they were they were in fact discovering and finding phage and so it became this because bacteria were killing people on at a regular rate. I mean normal healthy people would die from bacterial infections and scourged children, for example, all over the world. There was great hope that this thing that was discovered was somehow going to prevent people from dying from bacterial infections. And there's even a book Lewis Sinclair. It's called Arrowsmith. They describe this process where this guy discovers basically what it amounts as phage. He's going to use it to save the world from a plague-like bacterium. And then what happened was people jumped into it really quickly industry sort of jumped into it. They didn't really know what they were working with. This was before the time of like very controlled trials. Very controlled science very wild west type of ways of doing scientific and it many of the early investigations of the use of phage didn't work. And so the American Medical Association essentially wrote it off as being too inconsistent, but the reason it didn't work is because of the nature of what it actually is. It's a complex organism that goes through a life cycle of infecting bacterium. And you have to understand that life cycle to help make it work. Now let's flip to antibiotics. Penicillin the activity of that drug was discovered in the late 1920s. That story is well known about the growing of the mold on the plate in a clearing bacteria. So what happened was there was an excitement around that. But it took 20 years almost 20 years actually about 15 and World War II soldiers were getting infections on their wounds with bacteria for a company to actually figure out how to synthesize penicillin chemically in the lab. Once that happened that changed the course of modern medicine because it became evident that you could very quickly make chemicals that killed bacteria, and it could be standardized and then that could be scaled up and you can treat millions of people by doing that.

And so everybody that was sort of a pharmaceutical company at that time jumped into this exact process. Find chemicals that destroy antibiotics synthesize them and standardize it and then scale it up. And that's the Golden Era of antibiotic discovery and making what we call the classic years of antibiotic discovery. But no one really realized that one day that bacteria would become they would change and throw that entire industry on its head. But society got ingrained in that process in that mentality that you had to make a medicine. It had to be a chemical structure. It had to be standardized and it had to be scalable and that's the only way you would make new medicines, right. So a lot of it really is history. This is what society sort of accepted whole generations believe that this was the way to do it and when you grow up thinking that that's the way you do it and something else is offered as an alternative. It's hard to change. In fact, you have to have a generational change in thinking for the sort of that to become the realization and a new way of doing things. But I think the other reason which is a lot less sort of lengthy of an answer is phage every phage in and of itself is a different biological entity and you cannot apply a universal process to all phage. And when we in fact try to do that, it fails we have to understand the properties of individual phages and tailor them to specific infections and to specific diseases. And that is where we will find the consistency. We need to sort of get excited about this as a treatment.When the old model is applied to phage like antibiotics, it doesn't work. So in order for phage to sort of become accepted we have to sort of reinvent a new model to evaluate them from and so it's really a two-part answer.

 Sabrina Green: So what do you perceive to be the future of phages and they're used to treat infections in humans or animals? And can you talk a little bit about TAILOR which is a project that maybe Anthony can talk a little bit more about. So, Dr. Trautner.

Barbara Trautner: The future of phage. It’s uncertain. It’s truly uncertain. I spent a lot of time thinking about it. Sometimes I jot down notes in the car. How would I have applied phage in this clinical situation. I’m on the medicine team right now at the VA. And I think about where would phage have helped us and where would they have not helped us? They have such a narrow therapeutic window. And the bacteria and phage tend to co-exist. So any particular bacterial strain is going to become resistant to the phage its exposed to fairly fast. So I feel there's going to be certain clinical scenarios where they're very helpful. In a few doses maybe for stabilization, but maybe not so much for most of the longer-term treatments and then there are other settings where someone suffering from an intractable infection is gone on for a long time and we may be able to tailor phage that help us and that's just help us gain ascendancy with the person's immune system working together along with antibiotics.

I don't think they going to have, they are not going to be a replacement for antibiotics. They don't work the same way as antibiotics and we're going to have to have very good clinical trials that are rigorous that test phage in these very various scenarios before we see them come into practice. That’s why I thought about the future.

Anthony Maresso: Yeah, and I'll bet that I agree and I would add two additional parts, which is I think there's a scientific part and then there is a medical part. I think the scientific future of phage that is the sort of study of phage is going to be rather robust. It's estimated that there are 10^31 total phage on planet Earth. Which is more than the noble amount of stars in the observed universe. Each of those phages estimated they have 70% of its genome uncharacterized. And in fact those genes have no annotation or known resemblance to anything that are in the databases. So one really interesting scientific part of phage research is we can use phage as the largest repository of unique biology on planet Earth. The genes that they encode are likely completely unique because of what they have to do to prioritize their life cycle dominant over the bacterial one.

And I think that will be a rich source of scientific investigation in the future. The medical one is going to be I think bore out by the science as Barbara mentioned clinical trials, but also the basic science needed to investigate how phage work whether they synergize with the antibiotics what elements of phage will be more effective and what context can we apply the phage to. I think when the research is performed and we have more answers along that line will have more clear answers as to what the future of sort of phage therapy will be.

Would you like me to comment on TAILOR?

Sabrina Green: Yes.

Anthony Maresso: Okay. So it's I'm glad that I have the opportunity to talk about something that we've done in the laboratory, which is this TAILOR initiative which stands for tailored antimicrobials and Innovative laboratories for phage research. So what Baylor College of Medicine is done is they've sort of taken some of our work and decided that they would invest in it. And so we were able to create this initiative whereby if anyone has any particular bacterial problem, and it doesn't necessarily have to be an infection of a patient an agricultural problem where bacteria are a nuisance. It could be an environmental problem contamination or just interest in phage biology in general, but certainly as it also applies to clinical medicine. What we're able to do is use basic science techniques to sort of enhanced properties of phage. Use directed evolution to make phage more specific to a specific bacterial problem and then learn about how we can adapt that to solve problems that bacteria cause in the real world and it's a great team of young scientists in my laboratory. Sabrina is a part of that. Dr. Trautner is a part of that. Dr. Ramig a virologist colleague is a part of that and Dr. Terwilliger who is the project manager and what we hope is that people will come to us with bacterial problems.

And sort of work with us to find ways in which we can apply phage to solve those problems. Maybe we'll get lucky and we will solve some of them problems. But what I think will come out of it is a lot of basic science that will help us learn about how we can tailor phage to be better at solving some of these bigger problems. And then also learning just about the natural history of phages. They co-evolved with bacteria, which is a fascinating topic.

So physicians that are out there that are listening to this. If you have a challenging clinical case where antibiotics are not going to work or they've been tried and there's really no other hope the FDA does allow in some cases the compassionate use of experimental therapeutics to try to save the life of patients. And in this case, we could adapt our phage to the specific bacterium that your patient has make sure it's safe and clean and doesn't have any undesirable properties and is efficient at killing at the bacterium and we can ask the FDA for permission to be able to use this as an experimental therapeutic for your clinical case. And that's one of the components that TAILOR is trying to bring so if you're interested in those possibilities, you can contact myself or email the TAILOR Group, which I think there might be links and stuff embedded in this podcast or you can contact Dr. Trautner as well. We'd be happy to try to talk about how we can help.

Sabrina Green: Okay, the last question since this podcast really goes out to students who are probably looking for labs to rotate in. Can you talk a little bit about the way that you approach mentoring you both have won awards or gained recognition for being really great mentors as well as researchers. So, Dr. Trautner, can you talk a little bit about your mentoring approach?

Barbara Trautner: I'd be glad to. Mentoring is my passion. I have several passions, but that's certainly one of them is one of the best things about being an academician is the opportunity to mentor why it means so much to me is because I was so lost as a fellow as an infectious diseases fellow. I felt that I just didn't know where I wanted to go next with my career. I had a young child. I had no sense of why I was bothering to complete the fellowship because I didn't know my career goal. I didn't really have a sense of what academic medicine would mean and I was saved from that morass by a really good mentor who was our ID section chief new at the time and met with me and basically sat me down and said to me Barbara you're destined to be in academics. This is what you're going to do and it was so helpful to me. I stayed in the fellowship. I did an extra year to learn how to do research. I applied for the career development award, ended up in the Ph.D program all because of that one good Mentor followed by subsequent really good mentoring team. So I want to deliver that to other people. I don't want them to feel lost like I was so I like to work a lot with people at the postdoctoral level, which is the clinical fellows because they still can take so many different career directions and they can use so much guidance in that but I have mentees from all levels including some in high school.

Anthony Maresso: It's very difficult question to answer but I think what I would say was there's just no greater honor than being able to being able to train the next generation of scientists. These individuals are going to be the future leaders of our country. And they will be the future leaders of our planet and we have some really big problems to solve not just in medicine but in population explosion, in averting wars, sustainable agriculture and probably at some point in the future interstellar travel. And all of that is going to require capable scientists and I view my role as just sort of passing the torch on.

If I had to give advice about an approach to take and I'm not so sure that this is the best approach but it is what has worked for me. It is that I think you have to have an absolute belief in the people that you are working with you have to believe in their skills and their talents and in their determination and that they are going to try to find ways in which they can better improve the state of all humanity.

That's going to be different for each individual person and you have to have a personality that is able to resonate with each of their individual personalities and never ever give up on them. That's a rule that I steadfastly go by is that you have to try to find what they're really good at enhance that and subtly try to improve upon their limitations and it is different for every person. It's an individual challenge of itself and I have to say that it is much more challenging than the science itself, but it is the most rewarding part by far.

Sabrina Green: Thank you, both for talking. But thank you. Dr. Anthony Maresso,  Dr. Barbara Trautner. I'll talk to y'all later.

Barbara Trautner: Well, thank you for including us for organizing this thank you Juan Carlos for working with us.

Juan Carlos: It's been a great pleasure having you both. It was a pretty awesome. I always learn something new and I'm just kind of pretty fortunate to be part of this effort. Thank you so much.

Maresso: Thank you.

Trautner: Okay, thanks. Appreciate it.