Phage therapy (featuring Dr. Katrine Whiteson)

24:26I totally have all those on top of my head also, yeah. Let's just hope you don't put those into a salad dressing. It sounded like a recipe. Oh, my gosh. Yeah, and there's other bugs that are not on that list that do cause a lot of trouble that I work on in my lab, for example. Like a lot of people with cancer and cystic fibrosis get lung infections from a bug called Stenotropomonas. Also, Burkholderia. Those are gram negatives. We sometimes call them water lovers. You find them in tap water. Like they can live in tap water. Isn't that amazing? And they can live in soil. So you're often exposed to them in water or outside.

25:03And if your immune system is compromised, they can cause a lot of trouble. Sorry, why is it amazing they can live in tap water? I can live in tap water. How long, though? I mean, it's true. Water will sustain a human for like a little while. But at some point, you're going to need some calories. And you're going to get pruney. Oh, I see. You mean they can eat tap water. Like that's their only source of calories. That's amazing. I see. Okay. Exactly. Wow. That is amazing. Like if you pick up a bottle of water at the store, it probably has some of those cells in there. And I don't mean to make people not want to drink water because when I hear that there's microbes in something, that doesn't creep me out.

25:37I'm just like, oh, cool. More friends. I'm happily, you know, living among them. So I'm not saying you shouldn't drink water, but it's probably true that bottled water has higher microbial load from those gram negatives compared to like even tap water. So when we say these infections cause trouble, do we mean that they are bad for humans or do we mean that they're more likely to be resistant to antibiotics? Those are, well, the list I just gave you are of common infections that are frequently becoming resistant to antibiotics in a way that's untreatable. So for each of them, there's annual statistics being compiled on a global level to talk about how many infections are caused each year and how many of them resist antibiotics.

26:23Sometimes meaning you just have to switch antibiotics a few times, but eventually you find one that works. And sometimes meaning that you like literally never find an antibiotic that works. And so there are a lot of people in the world right now who have chronic infections that they cannot clear. Like from urinary tract infections are a really, really big one. Sometimes lung infections, wound infections can last forever and just be very, very hard to treat. And they're hard to get the medicine to as well because there's poor circulation in wounds. So I hear your question, and I guess the answer is both.

26:59Those are bugs that, through human history, have always caused a lot of infections. Many of them are bugs that are normal parts of our microbiome under good circumstances. But if your immune barriers break down, which can even just mean a scratch on your skin, like you could be a healthy person who just gets a scratch, and then all of a sudden staph that was happily living in normal amounts on your skin can then cause a terrible infection. Well, I've discovered a new thing to fixate on tonight. That's what's going to keep me up. Let's take a break. And when we get back, we'll talk about harnessing viruses to try to kill bacteria now that antibiotics aren't really doing the job.

27:49Hi, it's Alec Baldwin. This season on my podcast, Here's the Thing, I'm speaking with more artists, policymakers, and performers, like composer Mark Shaman. Once you've established that you have the talent, it's about the hang. It's the pleasure of hanging out with the people that you're with. You know, Rob and I was always a great hang. We would sit in kibitz for hours and then eventually get around to the music. That's what I mostly think of when I think of him, the time together laughing. Lawyer Robbie Kaplan. The great gift of being a lawyer is the ability to actually change things in our society in a way that very few people can.

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29:39Estate sales, funerals, auctions are usually good. There's a lot of good men there. Grocery stores near gyms. Darcy Cardin. I remember being like, I know this is good advice, but I really don't want to do that. So you didn't take her advice? I didn't take her advice. Are you still friends with that woman? No. She actually was kind of toxic. Neil deGrasse Tyson. I spent my whole life looking up. I was a geek kid. I had a telescope at age 12. So you didn't have sex for a long time? Sherry Oteri. Were you a soap opera person? Young and restless. Okay. Well, first of all, you should know it's the young and the restless.

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32:05Okay, we're back. And Kelly is covering herself with bubble wrap to protect herself from the future of infections. I can't imagine a chronic UTI. That sounds awful. It does sound awful, doesn't it? Katrina has a salad dressing that'll fix that for you. Oh, my gosh. Oh, that's great. That's great. Or cranberry pills or something. But anyway, all right. So we talked about how antibiotics are not working anymore in a lot of cases. And so you work on phage therapies. So what is a phage? Phages are viruses that kill bacteria. And so just to back up, for every cell that we have on the planet, there's usually about 10 kinds of viruses that can infect it.

32:48So there's always viruses around that can infect every kind of cell, like that pepper or tomato on your plate. There's tons of viruses that can infect that. So similarly, for all of the bacteria that we've talked about, there's usually about 10 viruses or so that can infect that cell type. So the idea of phage therapy is to take the viruses that can infect bacteria and use them as a medicine, kind of like the enemy of my enemy is my friend. Do the viruses have viruses? Yeah, well, there's actually, maybe they do, actually. There's kind of little hitchhiker DNA pieces that could be considered viruses on viruses.

33:28So yeah, it never ends. Okay. And should we think of these viruses the way we think of our microbial community? Like, are they sometimes helping the bacteria, sometimes it's not so clear, sometimes hurting them? Or are they always invading and taking over? Is it always a negative relationship between the viruses and the bacteria? It's definitely not always negative. And I think one of the big lessons of the last few years of our field is that it's pretty hard to categorize them. There's more of a gradient. So there's sometimes very direct killing types of relationships. But there's also a lot of kind of infect and hang out for a long time kind of relationships.

34:04And the truth is there is no bacterial community in the world that doesn't have viruses in it. So we can't really talk about what it would mean to be a bacterial community without viruses. They're just part of the situation, you know. Viruses are here to stay, you're saying. They're here to stay, and they're a big part of how bacteria work. I mean, any time a bacterial community experiences some kind of stress, they're going to be enriched for the cells that can handle the stress. And viruses are going to be transmitting the information to help them do that. So a big part of how bacteria can adapt to new situations is that the viruses help them out by transmitting information.

34:40I don't know how to feel about this. At first, I was like, bacteria are a pathogen. They're hurting us. They're killing people. They're painful UTIs. Now you're talking about them experiencing stress, and I'm, like, sympathetic towards them. And so, like, what am I supposed to feel about bacteria, Katrina? I mean, most bacteria are not pathogens, like, by far. Like, I just named a couple bacteria that cause infections, which actually are usually healthy, normal parts of our communities. And then that doesn't even begin to talk about all the microbes in the world. Very few are pathogens. It's just the ones on the news are pathogens.

35:13They should write more positive stories about helpful microbes. Yeah, they should. I do see a lot of them, although they're not very good scientifically, but always. But OK, so if every bacteria has 10 viruses, does that mean that viruses are the most diverse and speciose life on the planet? Or are the same viruses infecting lots of different kinds of bacteria? They are by far the most diverse. That is exactly the thing to say. I mean, I've got all like there's so many cool analogies. There's more viruses than stars in the galaxy or grains of sand on the planets. I think it's 10 to the 31. If you lined them up head to head, they'd go to the edge of the galaxy back and forth a bunch of times.

35:58You know, it's a crazy number of viruses. Yes, they are super, super diverse. And you asked a really important question about how specific they are. Like, is a virus that infects one of those bugs, the Pseudomonas, also able to infect a different bug, the Staphylococcus or something like that? Typically, no. In fact, it's at a substrain level. Like, a phage that infects one Pseudomonas. What's a substrain? It's like a subtype of Pseudomonas. Oh, I see. Like any type of bacteria has genus and species names, you know, King's Plague, Chesson, Fine-Grained Sand, the taxonomy going down to genus and species.

36:35Oh, you learned a nice one. Yeah, there's probably less appropriate ones going around the schoolyard. Yeah, I won't repeat mine. Go ahead. And so there's even substrains. So like Pseudomonas aeruginosa is a genus and species name, but there's subtypes beyond that. and whether the phage infects is usually at a subtype level like that. And it's kind of interesting to think about it. I mean, the bacteria are constantly making small mutations to resist the phages. So the trait of resisting a phage turns on a dime. It's just one mutation can probably do the trick. So it's not like a big, complicated trait like using oxygen and then you would need like a whole bunch of different genes and it's like very conserved.

37:21And if you looked back in the history of bacteria, you'd see big movement towards like, oh, now they can use oxygen or something like that. Phage infection is like a tiny little thing. It's very easy to change it. It's at the tippy-tippy branches of the toxinomic trees. And so if there are all these viruses out there that are infecting bacteria and they're very specific to the bacteria, but a very small change in the bacteria can mean that they can't be infected by the viruses. Is there some vast ocean of viruses out there that can't infect any bacteria yet? And some mutation of the bacteria makes them, therefore, susceptible?

37:55Or do viruses only exist and propagate if they can use bacteria? Well, I think there is an ocean of viruses out there that never get to infect a cell. So they have kind of an unrequited dream of finding a host, and they just never do. However, the dark viruses, the lonely ones. But now you're making us sympathetic to viruses, Katrina. You are too empathetic. But so, yes, there's going to be viruses out there that never get to infect a cell. But the strategy of a virus is to make a bajillion copies with lots of variation and hope that, you know, several of them have the capacity to go and find a host in a changing world.

38:39You know, it's like rather than training one kid with lots of skills and hoping they'll find a job in a changing world, it's like you got to raise billions of viruses and a few of them will continue to be able to infect. And I mean, it's been going on for a long time and in a way it's quite stable. Like if I took samples from anybody listening to this podcast right now and then in five more years took another sample, most of the gut viruses would would still be there. They might have evolved. Even 1 % to 3 % of their genome could have changed in a new direction. But I would be able to recognize them as themselves.

39:18So it's not like it's this raucous thing that's turning over and becoming a totally different thing all the time. There's some stability there, especially within the individuals. Each of our guts is like a little chemostat with tons of virus and bacterial evolution happening all the time. And it drifts around a bit, but it's quite stable in some ways. So we are like the interlopers, the weird ones in a viral world, right? That's certainly one way of looking at it. I mean, I think we have some advantages. I think consciousness does have, does distinguish us from viruses. There's days when I'd rather not have consciousness.

39:56But anyway, okay, so we've got viruses and some of them are bad for bacteria. How do we harness that to fight bacteria? So basically, the way that phage therapy has worked since even before we had antibiotics, so we've been doing this, phages were discovered in 1915 or 1917, depending how you look at it. And what we do is if you have a bacteria causing an infection, you use that as a hook and you go hunt for phages in a sample that has a lot of microbial activity to it. wastewater is a popular place to hunt, but freshwater ponds, puddles in front of your building. Wastewater is such a euphemism.

40:41I mean, you're talking about poop to pills, right? We're like finding medicine in sewage. Sewage is such a concentrated way to grab the microbes of humanity that it's a very tempting place to look. Because it's going to represent a lot of people. Like when we were doing our wastewater sequencing project during the pandemic, we were getting eight samples per week from Southern California wastewater treatment plants that represented 16 million people. Wow. From just eight samples. You are the queen of silver linings. Sewage is so tempting, said nobody ever. Anyway. Maybe we're not going to put you in charge of marketing and flavors for the new salad dressing company.

41:24So you were saying you have a bacteria you're looking to target, then you go out and you search extensive communities of viruses and you're trying to find one that will kill this particular bacteria? Exactly. So you take the infecting cells, you mix them with some wastewater, and then we use a technique. I mean, I need slides, man. This is hard on a podcast, but I want to show you guys pictures. But you make a plate of the bacteria mixed with the material that you hope has phages in it. And an important thing to say is that we filter it. We try to get the cells out of there. So it's just viruses left behind because otherwise you might imagine everything from the whole wastewater treatment plant growing on your plate, but actually you filter and hopefully there's viruses in there that infect your cell.

42:13But it's a mystery every time. Sometimes we spend six months hunting for a phage for one strain, even though I've got like really good people with lots of experience and I've got tons of great wastewater. I'll tell you that. So it's sort of like you have a lock and you're putting it in a bag of keys and shaking it around and hoping one of them goes in. Yeah. And then you get more experience with knowing what kinds of wastewater treatment plants are enriched for the bugs you care about. Like for our Steenotropomonas project, the wastewater in Escondido is like amazingly good. So if I get a Steenotropomonas infection, I'm like telling the students, please get the Escondido wastewater.

42:49What are they eating in Escondido? Or is it because of like an agricultural influence? I don't know. I would love to know the answer to that. But I can tell you it's been true for years. And lots of other labs failed to find stenotropomonas phages. But when we use Escondido wastewater, we've even sent our Escondido wastewater to collaborating labs. And they've also succeeded. It's liquid gold. Yeah. So then if you're lucky, you'll come in in the morning and you'll see a white bacterial lawn. And then you'll see these clearance zones on the plate. Those represent the phages. So if you get one of those, then you have a manufacturing project on your hands.

43:25Then you have to get the phage into big enough amounts and clean enough amounts. Wait, back up and explain what you were talking about there. A white bacterial lawn? So you'll have a plate of bacteria that look white. So you'll have like a flat white background. Why do they look white? Well, some bacteria are a little bit yellow or most bacteria are white or yellow. Sometimes they turn a little blue. But the point is you have a clear growth of cells on your plate. And then you can see with your naked eye that there are clearance zones from the viruses. And so that represents if one virus infects one of the cells on that plate, it will keep replicating and chewing up and eating and breaking the cells.

44:08So you'll get a clearance zone that's visible to the naked eye. I mean, obviously one virus is not visible to the naked eye, but what is visible to the naked eye is it's called a plaque. And it's a bunch of cell death caused by the virus in one little zone of the plate. And you can see that. And how do you know which virus has done it? You don't. You just know it looks like a virus. And if you've done it for a long time, you start to get familiar with the shape and the size of the plaque, the clearance zone. You can usually distinguish it from an air bubble or something like that, but not always.

44:43So it's definitely still an identification project once you get the plaque. But that's kind of step one. So really in my lab, if someone sends us, every week or two we get a new isolate into our lab where a doctor has a patient who has an antibiotic-resistant infection and they want to know, do we have a phage? So the first thing we do is we reach into our freezer, where we already have about 200 phages, and then we'll see if one of the ones that infected a similar strain can infect this new one. That's the easiest answer, because then we'll have already sequenced it, we'll know what it is, it's a big head start.

45:19But it's not uncommon, I'd say easily half the time, that none of the phages we have can infect. So then we do a new hunt in wastewater. And you have like your own personal lab library, like the ones you're talking about in your freezer. There's another lab somewhere else to have a different set. Another lab has a different set. This is like Katrina's personal phage arsenal. That's right. Yeah. And it's the way that you protect the information is really complicated. And we're all everyone's always changing their mind about that. My general attitude has been to be very open. And if somebody at another university needs one of our phages, I just send it to them.

45:53But we could be shooting ourselves as a community all in the foot because we're removing the capacity to make money off of them. So then nobody would ever invest. And what we need is for like real investment to get this thing off the ground, you know. All right. So back on the process here, you have the isolate, you scan through all your phages by just like mixing them together and seeing if one of them kills your bacteria. Maybe you have to go out to Escondido or somewhere else to find more phages. But now you have one that you think kills the bacteria. What do you do next? Then we purify. We have to like continue propagating and purifying.

46:28Most phage preps are contaminated in some way. It's actually very hard to get a PrEP that has just a single phage in it because they come out of these communities with a lot of different members. So step one is propagating where you pick the plaque and you reinfect bacteria. And it's like a 24-hour project each time. And you do that easily like three or four times. And some phages will kind of peter out at that point and reveal themselves to be hard to work with. And so if you have multiple different types emerging on your plate, you just abandon the ones that are difficult to deal with because what you want are easy to deal with phages.

47:07Difficult to deal with? Like they send grumpy emails late at night or what's going on? Like they one day they make a beautiful plaque and then the next day, even though you did everything exactly the same way, as far as you know, it just doesn't do anything. And then you're like going back to the plate from two days ago and hoping you can get it to cooperate again. That kind of thing. It's biology, so it depends. Yes. And by beautiful plaque, you mean like one day it beats the heck out of the bacteria and the next day it doesn't seem to kill them at all? Yeah, like maybe you'll get a nice big visible plaque, which means it's easy to pick so you can get material to work with for the next day.

47:41And then the next day your plate has nothing on it. So you're like, where did it even go? So each time you're picking the viruses that killed the bacteria and putting them onto a new plate. Exactly. And hoping to get a pure culture eventually. Exactly. And then you find out all these finicky things about how to deal with them. Some viruses prefer to grow in liquid. Others prefer to grow on a solid plate. Others do really well when the cells are multiplying quickly. Others do better when the cells are like kind of overnight growths that got tired out and we call them stationary phase. You know, they're like not as actively growing anymore.

48:17And viruses have all different mechanisms of entry and preferences for metabolism. So all of those things, you don't know them about your new virus yet. You're just like trying to propagate it. So then we'll do all kinds of things where we'll do temperature gradients and different types of media growth. And we'll try like triangulating all the conditions to learn what this particular virus likes the best. So then we can do a better job of propagating it in successful conditions. All right, so we've learned how to make a virus happy. And when we get back, we'll talk about actually giving those viruses to people.

49:16and anything else in the depths of their mind. It all happens on my show, Therapy Gecko, where we have real conversations just like this. Sometimes I'll have my girlfriend pre-chew spicy food and kind of baby bird it into my mouth. Is that weird? This week is Human Connection Week. We're taking a peek into the lives of various strangers who found my phone number online. We'll hear their funny moments, their difficult ones, and their unexpectedly profound ones. These are real conversations with real people figuring out life one call at a time. So if you're trying to get out of your own head and into someone else's, this is the podcast for you.

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51:04This season, we've got some awesome guests ready to dole out advice. Guests like Tiffany Haddish. kind of slide into people's DMs. I like Bumble. Also, girl, FarmersOnly.com. Estate sales, funerals, auctions are usually good. There's a lot of good men there. Grocery stores near gyms. Darcy Cardin. I remember being like, I know this is good advice, but like, I really don't want to do that. So you didn't take her advice? I didn't take her advice. Are you still friends with that woman? No. She actually was kind of toxic. Neil deGrasse Tyson. I spent my whole life looking up. I was a geek kid. I had a telescope at age 12.

51:42And so. So you didn't have sex for a long time. Sherry Oteri. Were you a soap opera person? Young and restless. Okay. Well, first of all, you should know it's the young and the restless. I can't even believe you're mispronouncing the title. Some of us abbreviate it because we've been so weird for so many years. T.S. Madison. Are you into poly? No, no, I don't think so. No, I could have told you no on that. Girl, why are you not into poly? Just based on what she's wearing and the way her hair is styled. She was not in a poly, okay? You're a trap poly. Anna Faris, Dave Franco, Madeline Klein, Hannah Gadsby, Adam Scott, Wanda Sykes, and more.

52:22Listen to Dear Chelsea on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. What did Black music, food, and culture teach us about who we were becoming? 2016 was sort of that last era of monoculture where we still consumed things in community. From Beyonce and Rihanna. Everybody wanted to be Beyonce. I don't think we'll ever see another Rihanna. To soul food, memory, identity, and the stories we carry through Black culture. What does it mean to be Black and eat in America? So we were this group of people who knew how to work the land, who knew how to live with the land. We make it do what it do.

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53:31Okay, we're back and we're hearing about how Katrina's lab might save somebody who's out there with a really difficult infection. whose doctor emails her and asks her if she's got something cooking up in the freezer that can kill their bacteria. So we've heard about how you find a phage that can help infect your bacteria. You purify it, you isolate it. How do you actually go all the way to putting it back in the human and treating them? Well, that's a really big question, but it's actually an old question. So since around 1920, especially in the former Soviet republics, phages have been used as medicine since before we even had antibiotics.

54:08And they were actually used in the Western world, you know, before the era of World War II as well. Like, for example, when Elizabeth Taylor was filming Cleopatra, I think she was in the UK, she got a terrible staph infection and they used phages to help clear her infection. Wow. There's a lot of stories like that from around that time. And so at the Eliava Institute in Tbilisi, Georgia, which is probably the most famous of these centers, they've been using phage therapy to treat infections for more than a century. And so it's a process like I just told you about. They have a much bigger bank of phages than I do, I'm sure, but they will find a phage.

54:46If one of their standard ones doesn't work, they'll go find a new one and they prep it and give it to you. But in the United States, there is no approved way to use phages. It's not sold. There's no FDA-approved medication that your doctor can prescribe. So all of it is happening through labs like mine and through applications to the Federal Drug Administration asking for an exemption, either as an emergency authorization or as a compassionate use exemption. So it has to be a situation where somebody's in really dire straits and taking on the risk of an experimental treatment makes sense. So in my lab for many years, I've been growing up these phages out of wastewater.

55:32And people were sometimes sending me their patients isolates and asking if we had a phage. And we almost always succeeded. That was not the barrier. But usually the person would either get better or pass away before we could get the phage prepped in order to help them. And that went on for years. And every time I would have a student who was such a good spirit and would spend the whole weekend working really hard to get the phages, and we'd be like so proud of the fact that we had one, but then it wouldn't actually help anyone because the whole process is too slow to help someone in really dire straits.

56:04So about a year ago, I went to the infectious disease department grand rounds at UC Irvine, where I work. And I talked to all the doctors about it. And I got a lot of help from Jessica Satcher of the phage directory. This was her idea, I think, actually. And we talked about how we should aim for people who are not quite so acutely ill, people who have a more chronic infection where their life would change and be improved if we could help them, but where if it took us like six months or a year to get all the approvals and to prep the phage, that would be okay. So that was April 2024. So since then, I've had 10 cases.

56:41We found phages in every single one. But only once have we gotten all the way to the FDA approval and actually give the phage to a person step. And it's all thanks to a student named Ritwick Kumar. He's really the reason this all happened. So he personally found, well, with a team of other students and a medical resident who joined our lab as a volunteer, actually, Ritwick hunted for a staph phage for the patient I'm talking about for about six months and never found one. Then the first week our new medical resident Alexandra showed up, she found a phage. So there must have been something different about her technique or the patch of wastewater we used that week or something.

57:21Anyway, we got a wonderful staph phage. We named her Ludmilla. And Alexandra named her Ludmilla. Yeah. And so since last summer, we have been prepping this phage Ludmilla to help a patient at the UCI Medical Center who has a chronic sinusitis with MRSA, methicillin-resistant Staphylococcus aureus, in their nose. And the doctor felt that it was a good case because the patient is getting frequent fevers. And so their quality of life is very affected, but they're stable enough that if we took six months or a year, it would be okay. And that is how long it took. So I actually sent Ritwick to my friend Daria Van Tynes' lab at Pitt to learn how they prep the phages because we were a little new at it.

58:07And I wanted to make sure that we were getting good advice and he could like watch somebody else doing all the steps. And then we also chose a gram-positive bacteria, Staphylococcus, because it doesn't carry endotoxins, which are really hard to purify out of bacterial preps. So it kind of made the process simpler by starting with a gram positive. Anyway, so Ritwick made a big batch of these phages. He stewed up some Ludmilla soup. He stewed up some Ludmilla soup, and then he filtered out all the stuff that could cause trouble. And I mean, I probably should not go into so many details about the protocol, but ask questions if you're interested.

58:45And so we prepped up the phage in a safe way. And then we actually even sent it out to a third-party lab to test for sterility and endotoxin. Because I didn't want it to be just like, yeah, me and my students think this is really clean. I wanted it to be like official, you know. And that's actually required by the FDA as well. And so once we had all that stuff done, we made this 50-page document and sent it to the FDA asking for authorization to use the phage. Actually, it was very interesting. Initially, we wanted to use the phage in an IV form, and the FDA came back and suggested instead that we do a sinus rinse, which I think was a really smart move because there's less chance for immune reaction.

59:29I don't have high expectations of problems with this, by the way. I mean, beyond the Eliyava Institute's century of experience, now in the United States, there's been several hundred cases in the last couple years, and I'm not aware of any adverse events. And by that, you mean nobody's had like a weird immune response to getting viruses put in them. Like everybody's fine. Maybe it doesn't kill the bacteria, but it doesn't hurt the people. Exactly. The person doesn't have a negative reaction to the treatment so far. I mean, it's still experimental, but so far there haven't been people having negative reactions.

1:00:03Great. What an amazing bespoke process, though. Like a lab with a student focused on one patient for months and months and months. It's a huge process and all this application. All right, so tell us what happened. Yeah. Did Lyudmila help? Well, I don't know yet. Yesterday, it's been three weeks. So it's a six-week treatment process. So it's daily sinus rinses for six weeks. Good news, nothing bad has happened. But really, we won't know. I mean, I think it's possible that they're feeling a little bit better. But they're also getting antibiotics at the same time. So the moment of truth will come about three to four weeks.

1:00:40after the six weeks treatment, because usually after the antibiotics are stopped, the fevers come back. So we're going to wait to see if the fevers do not come back at the end of the six weeks. All right. Well, we're recording this episode in mid-August, but we're going to post it later. So just before it posts, we'll get an update from Katrina on how this is going. So listen at the end of the episode for a more recent update from Katrina. Oh, what a good idea. I'm excited. But there's, I mean, there are actually a lot of interesting cases to follow. In fact, I was at the Evergreen Phage meeting in Knoxville, Tennessee last week, and I met a man who has been coming to the meeting a couple times who had a really terrible E.

1:01:19coli infection. And he actually traveled to the Eliava Institute in Tbilisi, Georgia, where they do these phage treatments. They cooked up a specific phage just for his infection because none of the ones in their bank were effective. and the doctors there had him do three 20-day courses of three times a day phage treatment and it wasn't until the second 20-day course that he started to feel better and then his bacterial load in his blood dropped so it's not necessarily that you would see a big effect in the first couple weeks like in his case at least it took several times and he wrote a book about it he's been on a lot of podcasts.

1:02:00It's a really, really cool story. So it's so cool that it worked for him. And if you look at the summary of some of those hundreds of cases that have been going on lately, it looks like 75 to 80 percent of people have a positive response as in like their infection has helped. Wow. But it's still very early days. I mean, as you say, Daniel, it's like kind of crazy to imagine that there's an individual lab customizing a treatment to each person. But on the other hand, the skills it takes are not that crazy. Like, I don't understand why we wouldn't have phage therapy clinics to be able to do this for people.

1:02:34Like, the resources are not that intense. The know-how is, you know, something that a good student can learn how to do. And we've known about this for 100 years. There's an institute in Georgia. Why isn't it more common? Like, why doesn't the U.S. allow this to happen all the time? I think it's a medical history question. I think we just went down a road using antibiotics, and they were approved into the medical system that we have. And it's a very different system. For antibiotics, there's a few dozen molecules. So it's possible to approve each one of them in a trial that these days would cost$100 million to get a drug through a phase three clinical trial.

1:03:14You can't really do that for every single phage, obviously. It's possible that the FDA will approve the preparation methods that we use, and then that would work for multiple different kinds of phages. But using the model of clinical trials that we currently have for approving drugs won't work for phages because you need different ones for each infection. So that's the real reason that it's not happening as much right now, I would say. How do you see it scaling up? Like, is there a future in which people have individualized medicine where I don't need Katrina and her lab, like, working on me individually?

1:03:49It's, like, roboticized or automated? Or how do we make this more widespread? It could be that we can develop, evolve or engineer phages that have broader host range so that we would only need a relatively small number of phages to cover most common infections. So that is certainly one possibility. That's a science question. I don't know if that's possible or not. But like in my own lab, we often do experiments where we evolve our phages to try to have broader host range to be able to infect more different subtypes of the same bacteria. You could also use molecules to try to assist the infection, and that might make one phage work in more context.

1:04:30Those are like two main research areas in my lab, actually. So that's possible. That's still a science question. But then even just using exactly the model of the Eliava Institute, I really love that idea. I just don't know how it would work in our current health care system. Maybe it has to be more like the way that supplements are sold, where they're generally regarded as safe. and so people could use phages as a kind of augment, like an addition to their antibiotics. Uh-oh, are we walking towards the podcast supplement industry that so many people get sucked into? We are not peddling supplements here.

1:05:07I was thinking more like a, I think like a wellness spa. Like apparently the Eliab Institute is an integrative health center where you get a massage every day and you meet with a team of doctors and psychiatrists and everybody helps you get better. And so, heck, yeah, exactly. So like, hey, we're in sunny SoCal. Maybe we should make a clinic. Some of us. Yeah, that's right. Can we talk a little bit more about the trade off? So you were talking about how your lab is trying to evolve the phages to be able to attack more kinds of bacteria. So two thoughts. One thought is that we talked earlier about how each phage is usually specialized on one species or even strain of bacteria.

1:05:45So I imagine it's very hard to evolve it to be more of a generalist. And then two, one of the benefits of this technique to me seems to be that you don't wipe out the rest of your bacteria. You can maintain your microbiome and just target the bad guy. So what are the trade-offs with trying to make a more general phage? Well, a more general phage would likely still be way more precise than an antibiotic. So if you were to take a phage that can kill most of your Enterococcus fecalis or pick one of those escape pathogens, that would still leave tons of other bacteria alone in a way that antibiotics really never do.

1:06:25So I think it would still be way more specific, even with a more generalist phage. So then the question is just whether we can evolve those generalist phages. For some industrial applications, there has already been signs of success for that. Like, in fact, the deli meat industry and the food spoilage industry have been using phages for a long time. And I think that there's a lot of industrial know-how that I am not privy to that suggests that this has been possible. So I don't know, but I think that there are a handful of Staphylococcus and Listeria and phages that are used in the food industry that actually do have pretty broad host range.

1:07:06So it could be that we could use the same methods to make that happen for human medicine, too. But there's still, it's just a totally different regulatory framework than what we're used to for pharmaceuticals. pharmaceuticals. So it's an interesting thing. I'm so curious if in 10 years we're going to have this all figured out and it's going to be widespread or if it's still going to be this kind of backwater. It's hard to know. It feels like there's a sea change right now, that there are now hundreds of clinicians that are very interested. But on average, if you go to your doctor and ask about phage therapy, they're probably not going to have heard of it, you know, or not know much.

1:07:42And in that scenario, could phage therapy be a victim of its own success? I mean, if you have these phages, you start using them on bacteria, are you then just going to end up with bacteria that are resistant to your phages? Couldn't it suffer the same fate as antibiotics? Yes, bacteria will evolve resistance to the phages, and that's exactly the same problem we have with antibiotics. You're right. I guess I look at it like the bacteria and phages have been in these arms races through the ages. And what you're trying to do in an infection is to give the immune system a leg up. And so in an acute sense, what you need is like a one-two punch and you could use antibiotics and phages at the same time.

1:08:27And you get in there and you tap the infection down a bit and you just give the immune system a moment of breathing room so that there's more chance for the human to survive the battle. You know, so. So, yeah, it's true that there could still be resistances arising to phages. But when people use that argument, I'm always like, hey, well, antibiotics, you know, bacteria resist antibiotics, too. And that didn't stop us from making good use of them and figuring out treatment plans that set things up so the human can succeed. So I think we just need to learn how to do that, which is very early days.

1:09:02As you can imagine, we've only used phages like, you know, a couple hundred times probably in the United States in the last decade. So it's not like if people ask you questions like, oh, should we use this dose or that dose or this treatment time or that treatment time? I mean, we do not know the answer to things like that yet. there's a final question we have to ask which is are there bacteria in space with phages and are aliens using phage therapy how how would how would you uh phrase the alien question this time around no i've trained you well kelly that was perfect yeah do aliens have viruses katrina well am i in the whites and institute now yes yes we'll send you some salad dressing yes Oh, my gosh.

1:09:47Well, we definitely have brought Earth's microbes out to space, although there is a whole division of NASA aiming towards preventing that from happening. So we work hard not to, but microbes are everywhere. So, of course, we've brought some out to space. So there's definitely going to be some phages out there would be my guess. I mean, they're probably not going to survive long. So would they make it to where aliens are? I would say no. No, but would aliens have their own native viruses? Do you think viruses are a common feature of life everywhere in the universe? Yes, I definitely do. I mean, I think most life will start from little self-replicating things like RNA world.

1:10:27I mean, that's the only model in my head. So, of course, I need to meet an alien who has a different model in their head to contradict it. But I could imagine a totally different type of life emerging with the same order of events where you start more from little self-replicating things that essentially are viruses. And in general, yeah, it's hard for me to imagine an ecology that doesn't have infection and viruses going on. So then actually my last question, Katrina, is where do your sympathies lie? I mean, you are growing up these phages. You're attacking the bacteria, but you're also talking about the bacteria getting stressed out.

1:11:03Are you in the camp of the humans or the bacteria or the viruses? Really, where should we put your allegiance? I mean, I do not think you need to have separate allegiances. This is like a big team. Dodging the question. No, she's not. That's a perfectly valid answer. Okay, but here's what I'm saying. I think that the bacteria are invited when they are behaving themselves. I mean, I am not inviting crazy, infecting, drug-resistant bacteria. Those guys have gone too far, you know. So there are some limits to Katrina's empathy even. That's amazing. But like an average bacteria is not a pathogen. But yeah, the pathogens, they're like nihilists, you know, they're not invited.

1:11:46Amen. All right. Well, it has been a fascinating day here at Daniel and Kelly's Viral Universe. I always love having you on the show, Katrina. Thank you. Well, thank you for having me. And thank you guys for listening to Phage Therapy. And if your listeners have any suggestions about how our community should get phage therapy off the ground, we're really listening. All right, so it's August 25th, and we're checking in for an update on that patient. Katrina, what is the status of the patient that your lab developed a phage for? Well, it's week four out of six now. So the fifth week of treatment out of six will begin on Thursday.

1:12:24So we don't have any knowledge yet of whether it worked. We actually have to wait for a month after the end of the therapy to see whether the fevers return or not. And that's how we'll know whether the staph causing sinusitis in the nose has been dampened and hopefully taken out by this phage. All right. Well, I guess we're going to have to have you back on the podcast for a follow up episode to see how this stuff works. I would love that. Great idea.

1:13:16questions at danielandkelly.org. Or you can find us on social media. We have accounts on X, Instagram, Blue Sky, and on all of those platforms, you can find us at D &K Universe. Don't be shy. Write to us. I'm Nick Turturro. You probably know me from NYPD Blue, The Longest Yard, or Spike Lee's Black Klansman. And on my new podcast, Delivering Happiness with Nick Turturro, I deliver pizza to a new guest. I've shared a slice with everyone. From Seth Rollins. What are you doing with my belt? To Bill Burr. I don't think I've ever met somebody so exactly out of their mind as I am. And now we even have more great guests coming up, including the great John Turturro.

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