Phage therapy (featuring Dr. Katrine Whiteson)

Daniel and Kelly chat with Katrine Whiteson about how we can enlist viruses to kill infectious bacteria. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Daniel Whiteson?

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• 0:05Speaker 01

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• 1:21Speaker 02

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• 1:52Daniel Whiteson?

  There's a battle being fought every minute of every day. It isn't a traditional war on the battlefield between armies of soldiers. It's a battle within us between our immune system and invading microbes. And we're not alone fighting off pathogens. We have hosts of microbial allies. Inside our bodies are multitudes of microbes, some helping us digest, others starving out potential invaders. But until recently, infections were too often deadly, and there was not much we could do other than try to avoid them. Treatment options were thin. But almost 100 years ago, we discovered a powerful new ally.

• 2:33Daniel Whiteson?

  Some fungi were the enemy of our enemy, able to kill bacteria and halt infections. And so antibiotics became our friends. But bacteria respond and evolve, developing protections against antibiotics and overcoming them. It's possible again today to become infected by a resistant strain and for doctors to have no real treatment options. Is it time to recruit a new ally in the microbial war? Today, we'll welcome a visiting dignitary and expert working on the front lines to find microbes capable of killing resistant bacteria with techniques that can be tailored to produce the particular microbe needed to halt your individual infection.

• 3:16Daniel Whiteson?

  Welcome to Daniel and Kelly's extraordinarily individual universe.

• 3:34Kelly Weinersmith?

  Hello, this is Kelly Wiener-Smith. I study parasites and space, and I think probably maybe the second or third critter on our planet was probably a parasite taking advantage of the first.

• 3:46Daniel Whiteson?

  Hi, I'm Daniel. I'm a particle physicist and professor at UC Irvine, and I'm definitely the second most useful person at the Weitstein Institute for Advanced Science.

• 3:55Kelly Weinersmith?

  And the good news is today, we're getting the first most useful person back on the show. This is the third time Katrina has joined you and I, and I enjoy it every single time.

• 4:04Daniel Whiteson?

  Yeah, listeners seem to really Enjoy having her on. And of course, I love talking to Katrina. And she knows so much about so many fascinating topics, especially the topic we're tackling today.

• 4:13Kelly Weinersmith?

  Yeah. And today we learned a really fascinating fact about what kind of organism on our planet is the most common. And I was, I can maybe a little bit surprised. But so, Daniel, I'll give you a little quiz here.

• 4:26Daniel Whiteson?

  You were hoping she was gonna say parasites, weren't you?

• 4:28Kelly Weinersmith?

  Well, I mean, the answer is a kind of parasite, really, or pathogen, depending on how you define these things. So I felt very validated today during our conversation. But Daniel, if you had to guess, what order of animals, and remember, it's kingdom phylum class order, what order of animals has the most species in it?

• 4:47Daniel Whiteson?

  This is totally fair, because I do a pop quiz on our listeners all the time. And so here, I've had no chance to prepare.

• 4:54Kelly Weinersmith?

  Your turn.

• 4:54Daniel Whiteson?

  I'm gonna have to go beetles. Is it beetles or ants?

• 4:58Kelly Weinersmith?

  You have perhaps heard that folks think beetles are the most common organism out there. And there's, you know, claims that God loved beetles more than any other organism. And that's why there were so many beetles on the planet. But it looks like actually, the most common kind of animal is not a beetle. But it's like wasps and hymenopterans, because each of those beetle species is infected by one or more wasp that lays its eggs inside of those beetles. And so, yes, you have a lot of hosts, but you, as is so often the case, and we'll hear more about today, hosts usually harbor a diverse community of things that are willing to live inside of them and eat their insides up.

• 5:41Kelly Weinersmith?

  And there's often more of those than there are the hosts. Good luck sleeping tonight, friends.

• 5:45Daniel Whiteson?

  And those parasites have their own bacterias, and those bacterias have their own little critters that live inside them. And today, we're gonna be hearing about how that all works and how it might chart a new course for treatment for difficult infections in humans.

• 5:59Kelly Weinersmith?

  It reminds me of a poem that goes, "Great fleas have little fleas upon their backs to bite them. And little fleas have lesser fleas, and so add infinitum. And the great fleas themselves, in turn, have greater fleas to go on. While these, again, have greater still, and greater still, and so on."

• 6:21Kelly Weinersmith?

  Anyway, so there's always levels of infection going on.

• 6:24Daniel Whiteson?

  It's infection all the way down. It's amazing.

• 6:26Kelly Weinersmith?

  Sure is.

• 6:27Daniel Whiteson?

  And so on today's program, we have my wonderful wife and colleague at the Weitzin Institute, who is coming back to the podcast to tell us about how she personally is developing treatments against resistant bacteria.

• 6:40Kelly Weinersmith?

  Best Weitzin. Just kidding, just kidding.

• 6:43Daniel Whiteson?

  Totally 100% agree with you on that one. So then it's my pleasure to welcome to the podcast Katrina Weitzin. She's a full professor, recently promoted from associate professor, congratulations, and chancellor's fellow at UC Irvine, where she studies microbial communities and how they interact with their hosts. That's us, we're the hosts. She also holds a dual appointment at the Weitzin Institute for Advanced Science, where she's the director for wet lab science, not just stuff on the computer, and has won awards for her innovative salad dressing recipes and her energetic insertion of chia seeds into every possible recipe. Katrina, welcome back to the podcast.

• 7:21Speaker 04

  Thank you very much for the overly kind introduction.

• 7:26Daniel Whiteson?

  Well, if this whole podcast and science thing doesn't work out, I'm counting on you to launch a line of salad dressings featuring chia seeds.

• 7:34Speaker 04

  Okay, I could probably do that. I just hope this time people would like to have a second helping. That's all.

• 7:40Kelly Weinersmith?

  Is this an inside joke? Does Daniel not have second helpings of salad or something?

• 7:44Daniel Whiteson?

  No, no, Katrina was one time making salad and we didn't have any vinegar, so she drained a jar of pickles and used pickle juice in the salad dressing. And one of our guests called it a one helping kind of salad dressing.

• 8:00Speaker 04

  Only after they learned what I had put in there, they were gobbling it up just fine before I said anything.

• 8:05Kelly Weinersmith?

  Oh, I see. I see. You should never tell people what's in the food until the end of the meal, very end. But I imagine you could make a salad dressing with all kinds of like microbiome related claims. I would probably buy it.

• 8:17Speaker 04

  It's true.

• 8:18Daniel Whiteson?

  But today, we're not here to talk about how to make your salad tasty. We're here to understand how to stay healthy and what's going on inside all of us. And so we want to get to the topic of phage therapy, but let's set the stage. Remind ourselves what's going on with traditional antibiotics? So like, give us the very basics. When you take penicillin or you take amoxicillin, what's going on? How do those work? How do those help you combat pathogens?

• 8:43Speaker 04

  Well, that's a really big question because each antibiotic is a molecule that has its own type of mechanism. And so we now have dozens of different kinds of antibiotics. They each work in different ways. Some of them are called bacteriostatic. So they'll halt the growth of the bacteria. They won't directly kill them. And others are called bacteriocidal because they can actually kill the bacteria. But the point is that whichever antibiotic you're taking, the goal is that it's going to prevent the bacteria from continuing to grow and cause infection. And between the antibiotic and your immune system, hopefully you're going to end up clearing the infection within a day or two. You know, all of us have probably had the experience of taking an antibiotic and feeling better relatively quickly.

• 9:28Speaker 04

  And that's because the antibiotic is getting in there, stopping or killing the bacteria. And then your immune system helps clear the infection. And so we've all also heard stories about how before, around the era of World War II, when antibiotics became more widely available, people would often succumb to very normal infections that people survive all the time right now. So we've become accustomed to being able to survive infections that took people down before the era of antibiotics and around the time of World War II.

• 10:01Kelly Weinersmith?

  I like that. I like that a lot. For bacteriostatic stuff, is the goal here just that you are trying to make sure they don't grow anymore to give your immune system time to kill them? Or are you making it so they can't reproduce? And the goal is that they'll die of old age at some point?

• 10:19Speaker 04

  I think either of those would be good outcomes. So, yeah.

• 10:22Kelly Weinersmith?

  Okay.

• 10:23Speaker 04

  But the point is just the population of bacteria is halted in its tracks. And then your immune system has a better chance to catch up.

• 10:31Kelly Weinersmith?

  Got it.

• 10:31Daniel Whiteson?

  And last time you were on the pod, you were telling us about all the beneficial microbes that live within us and among us. When you take one of these things, are they somehow targeted? Targeted towards pathogens or the things that are hurting you? Or is it just like a nuclear bomb? And it's just killing all of your microbes?

• 10:48Speaker 04

  That's also nuanced because it depends on the antibiotic. But on average, antibiotics have broader spectrum, which means that they take out lots of different types of bacteria, or at least a subset of bacteria. And to be honest, I'm not a deep expert on exactly what each antibiotic can cover. But it's definitely the case that when you take antibiotics, you're likely to kill bacteria that were not causing any trouble at all. So there's there's pros and cons to that. The pro side, you don't have to think too hard about which antibiotic to take. The doctor can be like, well, your infection is probably kind of one of these types of things. And then this antibiotic will probably take care of the problem. So it's good in that sense.

• 11:31Speaker 04

  And to be honest, at the time when we started using antibiotics in the mid 20th century, we didn't really appreciate our microbiomes. We thought it'd be great if we could just all be sterile. So it was kind of viewed as a positive, like, yeah, just get rid of all that stuff. That's only causing trouble. And now we actually have more nuanced appreciation for the fact that we don't want to be decimating our microbes all the time. So now it's we kind of appreciate that you don't necessarily want these broader spectrum antibiotics taking everything out. And some are a little bit more targeted than others.

• 12:02Kelly Weinersmith?

  Totally OK if this question is too far afield and you want to shoot it down. But could we give an example of how one kind of antibiotic focuses in on one kind of bacteria or a group of closely related bacteria? I think that's pretty interesting. I guess I had mostly thought that when you take an antibiotic, you're probably wiping out just about everything. How do you get certain kinds of bacteria targeted?

• 12:24Speaker 04

  Some molecules are focused on certain subsets of bacteria. I mean, for example, tobramycin is a recently developed antibiotic that people with cystic fibrosis use to treat pseudomonas infections in their lungs. And so that has relatively targeted action. But of course, it can still, my understanding is that it can still kill other gram negative bacteria. There's, there's a few big categories of bacteria and some antibiotics target broadly those categories. So if you have a gram negative targeting antibiotic, then your gram positives will be protected. For example, and I know there's certain antibiotics that are used when you're trying to target the anaerobes, which have different metabolisms.

• 13:07Speaker 04

  So miripenem, for example, is something I hear doctors saying they're using to include coverage of the anaerobes. And, you know, for example, they've even shown that if you take antibiotics that do not target the anaerobes, that can protect you in the hospital because the anaerobes are the gut bugs that are producing all those healthy molecules when they digest your fiber. So sparing them by using antibiotics that do not target anaerobes can be protective. And then I think we did talk about this last time, but if you decimate all your gut microbes with antibiotics, which happens pretty frequently in the hospital, then you can be susceptible to other infections like the Clostridium difficile that causes recurrent diarrhea.

• 13:50Daniel Whiteson?

  All right, so for hundreds of thousands of years, if you got an infection, you scratched your leg or whatever, you are at risk of dying. And then for 50 golden years or so, we've had these powerful antibiotics to protect ourselves and to make parents more relaxed when kids are climbing on rusty playground equipment. But what's happening now? Why are we hearing so much about antibiotic resistance? Why are these things not working anymore?

• 14:18Speaker 04

  Great question. Well, to be honest, every time we've started using an antibiotic, within five or 10 years, we've found bacteria that resist that antibiotic. So this is not a new problem. This has been going on ever since we first started using antibiotics. So during the whole second half of the 20th century, you know, we got penicillin. And within a couple of years, we had, you know, bugs that could resist the antibiotic penicillin. But then we would come up with new antibiotics. And so during the second half of the 20th century, if you look at the timeline of the discovery of antibiotics, you see all this beautiful new stuff emerging from the pipeline of research every few years. So there were always new options emerging.

• 15:00Speaker 04

  There's a few reasons we don't really have that pipeline right now. One of them is just the financial structure of the way drugs are being paid for in our society. Because antibiotics typically are acute treatments. And so it's not a lucrative business for pharmaceutical companies to invest in the production of new antibiotics. Because, first of all, if we get a new antibiotic, the doctors are gonna conserve it. Because they don't want new resistances to emerge. They're gonna be like, oh, man, this is my lucky ticket. I'm saving this for the moment. I really, really need it. But that's gonna be completely the opposite of the profit structure you would need for a pharmaceutical company to be willing to invest. So, to be honest, it's a little bit of a financial reason, but we've had a real slowdown in the pipeline of the discovery of antibiotics.

• 15:45Speaker 04

  There could be something to the fact that we found the low-hanging fruit. But the truth is, the world of microbiology has so much diversity. It's hard to even begin to explain how little of it we have discovered. Like, we haven't even started to look at 99% of what's out there. So, it's very impossible to me to imagine that we don't have lots of options out there if we were to put energy into it. We just haven't really had the resources to put energy into it lately. And so, there's been really cool ideas for alternative financial structures that could help. Like, for example, there was a big meeting at the UN a couple of years ago where they were talking about having a subscription model where countries or pharmaceutical companies or even healthcare companies

• 16:28Speaker 04

  could pay into a system where they could have access to a certain drug with a solid rate. And then it didn't matter how much they actually used it. So then there would be a financial structure independent of the use of the drug. But, I mean, in comparison to the blockbusters like statins or Ozempic, you know, antibiotics are just never gonna be as lucrative. So that's a real problem. And then I guess another thing I absolutely have to say is that about 80% of the antibiotics used, at least in the United States, are in the context of agriculture. So while we do need to reduce the human use of antibiotics, and I obviously support antibiotic stewardship programs, the main way that we use antibiotics,

• 17:11Speaker 04

  and probably where a lot of the resistances are arising, is in agriculture. So that's where we could make a lot of gains if we could reduce the use of antibiotics in animals, which is a hard thing to do. There's really cool models, like in Denmark, they had to disrupt the relationships between farmers and veterinarians in order to stop the prescription of antibiotics, because if the farmer was working with their old buddy veterinarian and asking for a prescription, they would say yes. It was so hard to get out of the social pressure of doing something you are accustomed to.

• 17:43Daniel Whiteson?

  But is this because like cows are getting scratches and they need treatment? Or is it just like they're pumping antibiotics in because it makes them grow faster?

• 17:51Speaker 04

  Yes, exactly. Most of the antibiotics being used in animal agriculture, it's because the antibiotics help the animals grow faster, which in itself is actually a fascinating science question. Like, why does it make them grow faster? Maybe it takes some of the energy away from fighting infection, and then you can like put that energy into beefing yourself up, or...

• 18:09Daniel Whiteson?

  Literally.

• 18:12Daniel Whiteson?

  Or porking out a little bit, yeah.

• 18:18Kelly Weinersmith?

  I was reading about tuberculosis the other day, and you know, I think I said in a prior episode, like, oh, there's all these diseases we don't have to worry about anymore, like tuberculosis. And then I started reading about tuberculosis, and it's a huge problem in India. And there is recently a new antibiotic that, for these same reasons you mentioned, they've been holding back because they want to like, you know, make sure they can save it for the special cases or whatever. But there's all these people who need it now.

• 18:40Speaker 04

  Yeah.

• 18:41Kelly Weinersmith?

  But you know, they're worried about using it and antibiotic resistance building up. So our audience seems really interested in evolution. And so we don't need to get into it at like the molecular level, but could you talk a little bit about like the micro evolutionary process that results in antibiotic resistance?

• 18:57Speaker 04

  Yeah, definitely. In fact, I think it's kind of... Interesting to think about, you know, just imagine a pile of bacteria. Like, are you thinking about the fact that there's a bunch of diversity in there? Because each cell could be a mutant. Microbes have very high mutation rates. So in any given population, the standing diversity is quite high. Every time a cell copies, there could be a mutation in there. So when we talk about antibiotic resistant cells emerging, really what that means is that you put the selection pressure of the antibiotics onto an existing community of bugs. And some of them have intrinsic capacity to resist the antibiotic. So those cells are the ones that survive when you give the antibiotic.

• 19:42Speaker 04

  So I have a lecture slide that's in my brain right now that you guys can't see, where it's got like all different colors of circles for the different cells. And some of them are red for resistance. And that's already like that at the beginning, before you even took the antibiotic. Then when you take the antibiotic, some of those cells survive. So that, I think, is a conceptual difference between how most of my students think it happens when I'm teaching about this. So really, there's already resistance in the population. And when you give antibiotics, some of the mutations that are already there help the cells resist antibiotics. Now, how do they resist? Some of them have pumps that can shoot the antibiotic out of the cell so they can survive.

• 20:24Speaker 04

  Others have mutations in a part of the cell that the antibiotic is trying to target. So it's just like, kaping, it doesn't do anything. In fact, there's a really interesting diversity for the different types of ways that cells can resist antibiotics. It's not only the classics that you read about in textbooks. But overall, once those traits become enriched in a community, they can start to spread them to other cells nearby. You've probably heard about like the spread of antibiotic resistance. And it's true that bacterial cells are really good at sharing information. They can put the information into little circular pieces of DNA and shoot them around in the community. And then that will help neighboring cells learn how to resist the antibiotics too. So anyway, there's

• 21:10Speaker 04

  A number of different mechanisms for how cells are able to resist antibiotics. And that's usually a trait that already exists in the population and you're just enriching for it at first.

• 21:20Kelly Weinersmith?

  That's really interesting. So like as someone who studies parasites, when we think about resistance to drugs for parasites, you get, you know, like the hookworm that randomly is able, for whatever reason, to resist the medication that you put in there. And then they produce eggs that pass with the environment. And then more people get infected by this resistant to medication hookworm. But bacteria have the additional ability to be able to share the traits for resistance between themselves, which speeds up the rate of resistance moving through the population. Would that be fair to say?

• 21:50Speaker 04

  Yeah.

• 21:51Kelly Weinersmith?

  Ah, bacteria are tricky.

• 21:53Speaker 04

  Definitely. Yeah. Big time. They're very tricky. Yeah. And sometimes the trait for resisting antibiotics comes at a cost. And so if you take the pressure off and the antibiotics aren't there anymore, they'll lose that trait. But it's interesting, sometimes the same pressures like antibiotics that help the trait stay in place can come from other sources, like in a wastewater treatment plant, for example. There, well, there might actually be some antibiotics around, but there also might be like heavy metals or pesticides or other kind of intense molecules that sometimes the traits that the bacteria need to survive antibiotics can also help them survive other situations.

• 22:34Speaker 04

  So there's a lot of situations in our modern world that push bacteria towards having these traits that help them resist antibiotics.

• 22:42Kelly Weinersmith?

  Dread.

• 22:43Daniel Whiteson?

  I think there's a major misconception that I think you really helped untangle a little bit there, which is that the traits are already there. It's not like the community is seeing this attack and thinking, what can we do to defend against this? Let's brainstorm and come up with something. It's just selecting for the folks that already have, or the bugs that already have these traits.

• 23:03Speaker 04

  Exactly, yeah. I watched that light bulb go off in my classrooms my whole life, where I think a lot of students imagine that you add the antibiotic and then all of a sudden the bacteria start mutating in this crazy new way and then they have this crazy new trait or something. But it's interesting, like it's usually already there, it just becomes enriched. And of course, it can get passed around, too.

• 23:23Daniel Whiteson?

  And what kind of infections typically cause trouble? Are there some kinds that are more likely to have bacteria that are resistant?

• 23:30Speaker 04

  Yes, definitely. In fact, there's even an acronym that the global health organizations are constantly talking about. It's called the Escape Pathogens, which stands for Enterococcus, Staphylococcus, Klebsiella, Asinobacter, Pseudomonas, Enterobacter, and sometimes we say escapee to add E. coli.

• 23:51Kelly Weinersmith?

  I mean, I would have guessed, I would have guessed that's what that acronym meant.

• 23:55Daniel Whiteson?

  I totally have all those on the top of my head also, yeah.

• 23:59Daniel Whiteson?

  Let's just hope you don't put those into a salad dressing. It sounded like a recipe.

• 24:02Speaker 04

  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 Stenotripomonas, 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. And if your immune system is compromised, they can cause a lot of trouble.

• 24:35Daniel Whiteson?

  Sorry, why is it amazing they can live in tap water? I can live in tap water.

• 24:39Speaker 04

  How long, though? I mean, it's true, water will sustain a human for like, a little while, but at some point, you're gonna need some calories.

• 24:45Kelly Weinersmith?

  And you're gonna get pruney.

• 24:46Daniel Whiteson?

  Oh, I see. You mean they can eat tap water, like that's their only source of calories? That's amazing. I see. Okay.

• 24:53Speaker 04

  Exactly. 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. I'm just like, oh, cool.

• 25:07Kelly Weinersmith?

  More friends.

• 25:08Speaker 04

  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.

• 25:21Kelly Weinersmith?

  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?

• 25:30Speaker 04

  Those are...

• 25:30Kelly Weinersmith?

  Or both?

• 25:30Speaker 04

  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 your 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. Sometimes meaning that 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.

• 26:01Kelly Weinersmith?

  Wow.

• 26:01Speaker 04

  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 really, really big one. Sometimes lung infections, wound infections can last forever and just be very, very hard to treat. And they're, 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. Those 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

• 26:44Speaker 04

  skin, like you could be a healthy person who just gets a scratch and then all of a sudden, stuff that was happily living in normal amounts on your skin can then cause a terrible infection.

• 26:55Kelly Weinersmith?

  Well, I've discovered a new thing to fixate on tonight. That's, 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.

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• 29:52Daniel Whiteson?

  Okay, we're back and Kelly is covering herself with bubble wrap to protect herself from the future of infections.

• 30:01Kelly Weinersmith?

  I can't imagine a chronic UTI. That sounds awful.

• 30:04Speaker 04

  It does sound awful, doesn't it?

• 30:05Daniel Whiteson?

  Katrina has a salad dressing that'll fix that for you.

• 30:08Speaker 04

  Oh, my gosh.

• 30:08Kelly Weinersmith?

  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, what is a phage?

• 30:22Speaker 04

  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. So 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.

• 31:03Kelly Weinersmith?

  Do the viruses have viruses?

• 31:05Speaker 04

  Yeah, well, there's actually, maybe they do, actually. There's kind of little hitchhiker DNA pieces that could be considered viruses on viruses. So yeah, it never ends.

• 31:17Daniel Whiteson?

  And should we think of these viruses the way we think of our microbial community? Like, are they sometimes helping the bacteria, sometimes not so clear, sometimes hurting them? Or are they always invading and taking over? Is there always a negative relationship between the viruses and the bacteria?

• 31:31Speaker 04

  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. And 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?

• 32:02Daniel Whiteson?

  Viruses are here to stay, you're saying?

• 32:04Speaker 04

  They're here to stay, and they're a big part of how bacteria work. I mean, anytime 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.

• 32:27Daniel Whiteson?

  I don't know how to feel about this. At first, I was like, bacteria are pathogens. 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?

• 32:40Speaker 04

  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. They should write more positive stories about helpful microbes.

• 33:03Daniel Whiteson?

  Yeah, they should.

• 33:04Kelly Weinersmith?

  I do see a lot of them, although they're not very good scientifically, but always. But, okay, so if every bacteria has 10 viruses, does that mean that viruses are the most like diverse and specious life on the planet? Or is, are the same viruses infecting lots of different kinds of bacteria?

• 33:24Speaker 04

  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. You 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.

• 34:08Daniel Whiteson?

  What's a substrain?

• 34:09Speaker 04

  It's like a subtype of Pseudomonas.

• 34:11Daniel Whiteson?

  Oh, I see.

• 34:12Speaker 04

  Like, any type of bacteria has genus and species names. You know, King's plague chests on fine-grained sand, the taxonomy going down to genus and species.

• 34:21Kelly Weinersmith?

  Oh, you learned a nice one.

• 34:22Speaker 04

  Yeah, there's probably less appropriate ones going around the schoolyard.

• 34:27Kelly Weinersmith?

  Yeah, I won't, I won't repeat mine. Go ahead.

• 34:29Speaker 04

  And so there's even substrains. So like Pseudomonas originosus 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.

• 34:44Daniel Whiteson?

  Wow.

• 34:45Speaker 04

  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. And 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 toxonomic trees.

• 35:21Daniel Whiteson?

  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 could 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? Or do viruses only exist and propagate if they can use bacteria?

• 35:45Speaker 04

  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...

• 35:58Daniel Whiteson?

  The dark viruses.

• 35:59Speaker 04

  The lonely ones. But...

• 36:02Daniel Whiteson?

  Now you're making us sympathetic to viruses, Katrina. You are too empathetic.

• 36:06Speaker 04

  But um, so yes, there's gonna 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, you know, it's like, and rather than training one kid with lots of skills and hoping they'll find a job in a changing world, it's like you gotta 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

• 36:50Speaker 04

  another sample, most of the gut viruses would would still be there. They might have evolved, even one to three percent of their genome could have changed in a new direction, but I would be able to recognize them as themselves. So 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 individual. Just 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 it's quite stable in some ways.

• 37:25Daniel Whiteson?

  So we are the the interlopers, the weird ones in a viral world, right?

• 37:29Speaker 04

  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.

• 37:40Kelly Weinersmith?

  There's days when I'd rather not have consciousness, but but anyway, okay, so we've got, we've got viruses and some of them are bad for bacteria. How do we harness that to fight bacteria?

• 37:52Speaker 04

  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.

• 38:25Daniel Whiteson?

  Wastewater is such a euphemism. I mean, you're talking about poop to pills, right? We're like finding medicine in sewage.

• 38:32Speaker 04

  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, 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.

• 38:54Kelly Weinersmith?

  Wow.

• 38:54Speaker 04

  From just eight samples.

• 38:56Kelly Weinersmith?

  You are the queen of silver linings.

• 38:59Daniel Whiteson?

  Sewage is so tempting, said nobody ever. Anyway.

• 39:04Daniel Whiteson?

  Maybe we're not going to put you in charge of marketing and flavors for the new salad dressing company.

• 39:10Daniel Whiteson?

  So you're saying you have a bacteria you're looking to target, then you go out and you search extent of communities of viruses and you're trying to find one that will kill this particular bacteria?

• 39:21Speaker 04

  Exactly. So you take the infecting cells, you mix them with some wastewater. And then we, we use a technique. I mean, I need slides, man. This is hard on a podcast. I want to show you guys pictures.

• 39:36Kelly Weinersmith?

  It is.

• 39:36Speaker 04

  But, but you know, you, 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. Cause 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. But 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.

• 40:12Daniel Whiteson?

  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?

• 40:18Speaker 04

  Yeah. And then, then you get more experience with knowing what kinds of wastewater treatment plants are enriched for the bugs you care about. Like for our Stena Trupomonas project, the wastewater in Escondido is like amazingly good. So if I get a Steno infection, I'm like telling the students, please get the Escondido wastewater.

• 40:35Daniel Whiteson?

  What are they eating in Escondido?

• 40:37Speaker 04

  Or is it because of like an agricultural influence? Or 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 Stena Trupomonas phages. But when we use Escondido wastewater, we've even sent our Escondido wastewater to collaborating labs and they've also succeeded.

• 40:55Daniel Whiteson?

  It's liquid gold.

• 40:56Speaker 04

  Yeah. So then, once you, if you're lucky and 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. Then you have to get the phage into big enough amounts and clean enough amounts.

• 41:16Daniel Whiteson?

  Wait, back up and explain what you were talking about there. A white bacterial lawn?

• 41:20Speaker 04

  Uh huh. So you'll have a, a plate of bacteria that look white. So you'll have like a flat white background.

• 41:27Daniel Whiteson?

  Why do they look white?

• 41:28Speaker 04

  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, 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. So 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.

• 42:10Daniel Whiteson?

  And how do you know which virus has done it?

• 42:13Speaker 04

  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 way, the shape and the size of the, of the plaque, the clearance zone. You can usually distinguish it from an air bubble or something like that, but not always. So 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, which where we already have about 200 phages.

• 42:55Speaker 04

  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. But 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.

• 43:15Daniel Whiteson?

  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.

• 43:22Speaker 04

  Yeah.

• 43:22Daniel Whiteson?

  Another lab has a different set. This is like Katrina's personal phage arsenal.

• 43:25Speaker 04

  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. But 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?

• 43:53Daniel Whiteson?

  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?

• 44:09Speaker 04

  Then we purify. We have to like continue propagating and purifying. Most 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.

• 44:53Daniel Whiteson?

  Difficult to deal with, like they send grumpy emails late at night? Or what's going on?

• 44:57Speaker 04

  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.

• 45:11Daniel Whiteson?

  Hmm, it's biology, so it depends.

• 45:13Speaker 04

  Yes.

• 45:14Kelly Weinersmith?

  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?

• 45:19Speaker 04

  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. And then the next day, your plate has nothing on it. So you're like, where did it even go?

• 45:32Kelly Weinersmith?

  So each time you're picking the viruses that killed the bacteria and putting them onto a new plate?

• 45:36Speaker 04

  Exactly.

• 45:37Kelly Weinersmith?

  And hoping to get a pure culture eventually?

• 45:39Speaker 04

  Exactly. And then it, 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. And 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.

• 46:22Speaker 04

  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.

• 46:32Kelly Weinersmith?

  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.

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• 49:29Daniel Whiteson?

  Okay, we're back and we're hearing about how Katrina's lab might save somebody who's out there with a really difficult infection. This 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?

• 49:53Speaker 04

  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. And 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.

• 50:37Speaker 04

  And so they, 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. If 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. 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

• 51:21Speaker 04

  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 and 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. So about a year ago, I went to the infectious disease department

• 52:06Speaker 04

  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. We 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.

• 52:51Speaker 04

  Yeah, 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 staff 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. Anyway, we got a wonderful staff phage. We named her Ludmilla. And Alexandri named her Ludmilla. And, and so since last summer, we have been prepping this phage Ludmilla to help a patient at the UCI Medical Center

• 53:36Speaker 04

  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 Darié van Tijns' lab at Pitt to learn how they prep the phages because we were a little new at it. And 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

• 54:17Speaker 04

  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.

• 54:30Daniel Whiteson?

  He stewed up some Ludmilla soup.

• 54:31Speaker 04

  He stewed up some Ludmilla soup, and then he filtered out all the stuff that could cause trouble. And I mean, it's, I'm, I probably should not go into so many details about the protocol, but ask questions if you're interested. And 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. And 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? Yeah. 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.

• 55:16Speaker 04

  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. I don't have high expectations of problems with this, by the way. I mean, beyond the Eliyahu Institute's century of experience now in the United States, there's been several hundred cases in the last couple of years, and I'm not aware of any adverse events.

• 55:41Kelly Weinersmith?

  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.

• 55:49Speaker 04

  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.

• 56:01Kelly Weinersmith?

  Great.

• 56:02Daniel Whiteson?

  What an amazing bespoke process, though. Like, a lab with a student focused on one patient for months and months and months. What a huge process and all this application. All right, so tell us, what happened?

• 56:13Speaker 04

  Yeah.

• 56:13Daniel Whiteson?

  Did Ludmilla help?

• 56:14Speaker 04

  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 after 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.

• 56:50Daniel Whiteson?

  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.

• 57:03Speaker 04

  Oh, what a good idea.

• 57:04Kelly Weinersmith?

  I'm excited.

• 57:05Speaker 04

  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 of times, who had a really terrible E. coli infection. And he actually traveled to the Eliyahu 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.

• 57:48Speaker 04

  So it's not necessarily that you would see a big effect in the first couple of 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. It'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% of people have a positive response as in like their infection has helped.

• 58:14Kelly Weinersmith?

  Wow.

• 58:14Speaker 04

  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. Like, the resources are not that intense. The know-how is, you know, something that a good student can learn how to do.

• 58:38Kelly Weinersmith?

  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 US allow this to happen all the time?

• 58:48Speaker 04

  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. You 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.

• 59:33Speaker 04

  So that's the real reason that it's not happening as much right now, I would say.

• 59:38Daniel Whiteson?

  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? It's like roboticized or automated, or how do we make this more widespread?

• 59:52Speaker 04

  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 contexts. Those are like two main research areas in my lab, actually. So that's possible. That's still a science question. But then

• 1:00:34Speaker 04

  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 healthcare 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.

• 1:00:56Daniel Whiteson?

  Uh oh, are we walking towards the podcast supplement industry that so many people get sucked into?

• 1:01:04Daniel Whiteson?

  We are not peddling supplements here.

• 1:01:05Speaker 04

  I was thinking more like a, I think like a wellness spa. Like, apparently the Eliava 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...

• 1:01:18Kelly Weinersmith?

  Heck, yeah!

• 1:01:19Speaker 04

  Exactly. So like, hey, we're in sunny SoCal, maybe we should make a clinic.

• 1:01:24Daniel Whiteson?

  Some of us.

• 1:01:26Speaker 04

  Yeah, that's right.

• 1:01:27Kelly Weinersmith?

  Can we talk a little bit more about the trade off? So you were talking about how your lab is trying to evolve

• 1:01:32Speaker 04

  Yeah.

• 1:01:32Kelly Weinersmith?

  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. So I imagine it's very hard to evolve it to be more of a generalist. And then two, you know, 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 like maintain your microbiome and just target the bad guy.

• 1:01:57Speaker 04

  Yeah.

• 1:01:58Kelly Weinersmith?

  So like, what are, what are the trade offs with, with trying to make a more general phage?

• 1:02:03Speaker 04

  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. So I think it would still be way more specific, even with a more generalist phage.

• 1:02:28Kelly Weinersmith?

  Cool.

• 1:02:28Speaker 04

  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.

• 1:02:53Kelly Weinersmith?

  So Cool.

• 1:02:54Speaker 04

  I don't, 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. So 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. So it's, it's an interesting. I think 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 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

• 1:03:38Speaker 04

  not going to have heard of it, you know, or not know much.

• 1:03:40Daniel Whiteson?

  And 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?

• 1:03:54Speaker 04

  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. And 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?

• 1:04:36Speaker 04

  So, um, 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. As 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.

• 1:05:17Kelly Weinersmith?

  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 would you phrase the alien question this time around, Daniel?

• 1:05:31Daniel Whiteson?

  No, I've trained you well, Kelly. That was perfect. Yeah. Do aliens have viruses, Katrina?

• 1:05:36Speaker 04

  Well, am I in the Weitzin Institute now?

• 1:05:39Daniel Whiteson?

  Yes.

• 1:05:40Kelly Weinersmith?

  Yes.

• 1:05:41Daniel Whiteson?

  We'll send you some salad dressing, yes.

• 1:05:43Speaker 04

  Well, 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.

• 1:06:10Daniel Whiteson?

  No, but would aliens have their own native viruses? Do you think viruses are a common feature of life everywhere in the universe?

• 1:06:16Speaker 04

  Yes, I definitely do. I mean, I think most life will start from little self-replicating things like RNA world. I 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 any ecology that doesn't have infection and viruses going on.

• 1:06:50Daniel Whiteson?

  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. Are you in the camp of the humans or the bacteria or the viruses? Really, where should we put your allegiance?

• 1:07:06Speaker 04

  I mean, I do not think you need to have separate allegiances. This is like a big team.

• 1:07:11Daniel Whiteson?

  Dodging the question.

• 1:07:13Kelly Weinersmith?

  No, she's not. That's a perfectly valid answer.

• 1:07:16Speaker 04

  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?

• 1:07:34Daniel Whiteson?

  So there are some limits to Katrina's empathy even. That's amazing.

• 1:07:37Speaker 04

  But like an average bacteria is not a pathogen. But yeah, the pathogens, they're like nihilists. You know, they're not invited.

• 1:07:43Kelly Weinersmith?

  Amen. 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.

• 1:07:52Speaker 04

  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.

• 1:08:07Daniel Whiteson?

  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?

• 1:08:15Speaker 04

  Well, it's week four out of six now. So the fifth week of treatment out of six will begin on Thursday. So 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.

• 1:08:39Daniel Whiteson?

  All right, well, because we're going to have to have you back on the podcast for a follow-up episode to see how this stuff works.

• 1:08:44Speaker 04

  I would love that. Great idea.

• 1:08:52Kelly Weinersmith?

  Daniel and Kelly's Extraordinary Universe is produced by iHeartRadio. We would love to hear from you.

• 1:08:58Daniel Whiteson?

  We really would. We want to know what questions you have about this extraordinary universe.

• 1:09:04Kelly Weinersmith?

  We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you.

• 1:09:10Daniel Whiteson?

  We really mean it. We answer every message. Email us at [email protected].

• 1:09:17Kelly Weinersmith?

  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 and K Universe.

• 1:09:26Daniel Whiteson?

  Don't be shy. Write to us.

• 1:09:30Daniel Whiteson?

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