Latest / Daniel and Kelly’s Extraordinary Universe / Phage therapy (featuring Dr. Katrine Whiteson)

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Phage therapy (featuring Dr. Katrine Whiteson) · Daniel and Kelly’s Extraordinary Universe

• 0:07
  Speaker 1: There's a battle being fought every minute of every day.
• 0:11
  Speaker 1: It isn't a traditional war on the battlefield between armies
• 0:15
  Speaker 1: of soldiers. It's a battle within us, between our immune
• 0:19
  Speaker 1: system and invading microbes. And we're not alone fighting off pathogens.
• 0:24
  Speaker 1: We have hosts of microbial allies. Inside our bodies are
• 0:29
  Speaker 1: multitudes of microbes, some helping us digest, others starving out
• 0:33
  Speaker 1: potential invaders. But until recently, infections were too often deadly,
• 0:38
  Speaker 1: and there was not much we could do other than
• 0:40
  Speaker 1: try to avoid them. Treatment options were thin. But almost
• 0:45
  Speaker 1: one hundred years ago we discovered a powerful new ally.
• 0:48
  Speaker 1: Some fungi were the enemy of our enemy, able to
• 0:51
  Speaker 1: kill bacteria and halt infections, and so antibiotics became our friends.
• 0:57
  Speaker 1: But bacteria respond and evolve, developing protections against antibiotics and
• 1:02
  Speaker 1: overcoming them. It's possible again today to become infected by
• 1:06
  Speaker 1: a resistant strain and for doctors to have no real
• 1:10
  Speaker 1: treatment options. Is it time to recruit a new ally
• 1:14
  Speaker 1: in the microbial war? Today, we'll welcome a visiting dignitary
• 1:18
  Speaker 1: and expert working on the front lines to find microbes
• 1:21
  Speaker 1: capable of killing resistant bacteria with techniques that can be
• 1:25
  Speaker 1: tailored to produce the particular microbe needed to halt your
• 1:29
  Speaker 1: individual infection. Welcome to Daniel and Kelly's extraordinarily individual universe.
• 1:49
  Speaker 2: Hello, this is Kelly Windersmith.
• 1:50
  Speaker 3: I study parasites and space, and I think probably maybe
• 1:54
  Speaker 3: the second or third critter on our planet was probably
• 1:57
  Speaker 3: a parasite taking advantage of the first. Hi.
• 2:02
  Speaker 1: I'm Daniel. I'm a particle of physicists and professor at
• 2:05
  Speaker 1: UC Irvine, and I'm definitely the second most useful person
• 2:08
  Speaker 1: at the Whiteston Institute for Advanced Science.
• 2:10
  Speaker 3: And the good news is today we're getting the first
• 2:12
  Speaker 3: most useful person back on the show.
• 2:15
  Speaker 2: This is the third time.
• 2:15
  Speaker 3: Katrina has joined you and I and I enjoy it
• 2:18
  Speaker 3: every single time.
• 2:19
  Speaker 1: Yeah, listeners seem to really enjoy having her on. And
• 2:21
  Speaker 1: of course I love talking to Katrina and she knows
• 2:24
  Speaker 1: so much about so many fascinating topics, especially the topic
• 2:27
  Speaker 1: we're tackling today.
• 2:28
  Speaker 3: Yeah, and today we learn a really fascinating fact about
• 2:32
  Speaker 3: what kind of organism on our planet is the most common.
• 2:36
  Speaker 3: And I was I can maybe a little bit surprised,
• 2:39
  Speaker 3: but so Daniel, I'll give you a little quiz here.
• 2:41
  Speaker 1: You were hoping she was going to say parasites, wouldn't
• 2:43
  Speaker 1: you Well, I mean.
• 2:44
  Speaker 3: The answer is a kind of parasite really or pathogen,
• 2:47
  Speaker 3: depending on how you find these things.
• 2:48
  Speaker 2: So I felt very validated today during our conversation.
• 2:53
  Speaker 3: But Daniel, if you had to guess what order of animals,
• 2:56
  Speaker 3: and remember it's Kingdom Philum class order or of animals
• 3:01
  Speaker 3: has the most species in it?
• 3:03
  Speaker 1: This is totally fair because I do a pop quiz
• 3:05
  Speaker 1: on our listeners all the time, and so here I've
• 3:08
  Speaker 1: had no chance to prepare you turn. I'm gonna have
• 3:10
  Speaker 1: to go beetles? Is it beetles or ants?
• 3:13
  Speaker 3: You have perhaps heard that folks think beetles are the
• 3:16
  Speaker 3: most common organism out there, and there's you know, claims
• 3:20
  Speaker 3: that God loved beetles more than any other organism and
• 3:22
  Speaker 3: that's why there were so many beetles on the planet.
• 3:25
  Speaker 3: But it looks like actually the most common kind of
• 3:30
  Speaker 3: animal is not a beetle, but it's like wasps and hymenopterans, because.
• 3:36
  Speaker 2: Each of those beetles species.
• 3:38
  Speaker 3: Is infected by one or more wasp that lays its
• 3:42
  Speaker 3: eggs inside of those beetles. And so yes, you have
• 3:45
  Speaker 3: a lot of hosts, but you, as is so often
• 3:47
  Speaker 3: the case, and we'll hear more about today. Hosts usually
• 3:50
  Speaker 3: harbor a diverse community of things that are willing to
• 3:53
  Speaker 3: live inside of them and eat their insides up, and
• 3:56
  Speaker 3: there's often more of those than there are the hosts.
• 3:59
  Speaker 3: Good luck, sleeping friends, And.
• 4:00
  Speaker 1: Those parasites have their own bacterias, and those bacterias have
• 4:03
  Speaker 1: their own little critters that live inside them. And today
• 4:06
  Speaker 1: we're gonna be hearing about how that all works and
• 4:09
  Speaker 1: how it might chart a new course for treatment for
• 4:12
  Speaker 1: difficult infections in humans.
• 4:14
  Speaker 3: It reminds me of a poem that goes, great fleas
• 4:18
  Speaker 3: have little fleas upon their backs to bite them, and
• 4:22
  Speaker 3: little fleas have lesser fleas, and so add infinitum, and
• 4:26
  Speaker 3: the great fleas themselves, in turn have greater fleas to
• 4:29
  Speaker 3: go on, while these again have greater still, and greater
• 4:33
  Speaker 3: still and so on.
• 4:36
  Speaker 2: Anyway, so there's always levels of infection going on.
• 4:39
  Speaker 1: It's infection all the way down.
• 4:41
  Speaker 2: It's amazing, sure is.
• 4:43
  Speaker 1: And so on today's program we have my wonderful wife
• 4:46
  Speaker 1: and colleague at the Whites Institute who is coming back
• 4:48
  Speaker 1: to the podcast to tell us about how she personally
• 4:52
  Speaker 1: is developing treatments against resistant bacteria.
• 4:55
  Speaker 2: Best whites in.
• 4:57
  Speaker 4: Just kidding, just.
• 4:58
  Speaker 1: Kidding, totally undrescent agree with you on that one. So
• 5:02
  Speaker 1: then it's my pleasure to welcome to the podcast Katrina Whitson.
• 5:04
  Speaker 1: She's a full professor recently promoted from Associate professor, congratulations,
• 5:09
  Speaker 1: and Chancellor's Fellow at UC Irvine, where she studies microbial
• 5:13
  Speaker 1: communities and how they interact with their hosts. That's us,
• 5:17
  Speaker 1: we're the hosts. She also holds a dual appointment at
• 5:20
  Speaker 1: the Whitsun Institute for Advanced Science, where she's the director
• 5:24
  Speaker 1: for wet lab science not just stuff on the computer,
• 5:27
  Speaker 1: and has won awards for her innovative salad dressing recipes
• 5:30
  Speaker 1: and her energetic insertion of chia seeds into every possible recipe. Katrina,
• 5:34
  Speaker 1: welcome back to the podcast.
• 5:36
  Speaker 4: Thank you very much for the overly kind introduction.
• 5:42
  Speaker 1: Well, if this whole podcast and science thing doesn't work out,
• 5:44
  Speaker 1: I'm counting on you to launch a line of salad
• 5:48
  Speaker 1: dressings featuring chia seeds.
• 5:50
  Speaker 4: Okay, I could probably do that. I just hope this
• 5:52
  Speaker 4: time people would like to have a second helping that's all.
• 5:56
  Speaker 3: Is this an inside joke? Does Daniel not have second helpings?
• 5:58
  Speaker 3: Of salad or something.
• 6:00
  Speaker 1: No. No. Katrina was one time making salad and we didn't
• 6:02
  Speaker 1: have any vinegar, so she drained a jar of pickles
• 6:05
  Speaker 1: and used pickle juice in the salad dressing, and one
• 6:09
  Speaker 1: of our guests called it a one helping kind of salad.
• 6:12
  Speaker 4: Us only after they learned what I had put in there.
• 6:18
  Speaker 4: They were gobbling it up, just buying before I said anything.
• 6:21
  Speaker 3: Oh, I see, I see you. We should never tell
• 6:23
  Speaker 3: people what's in the food until the end of the meal. Yeah,
• 6:26
  Speaker 3: but I imagine you could make a salad dressing with all
• 6:28
  Speaker 3: kinds of like microbiome related claims.
• 6:31
  Speaker 2: I would probably buy it.
• 6:32
  Speaker 4: It's true.
• 6:33
  Speaker 1: But today we're not here to talk about how to
• 6:35
  Speaker 1: make your salad tastey. We're here to understand how to
• 6:38
  Speaker 1: stay healthy and what's going on inside all of us.
• 6:41
  Speaker 1: And so we want to get to the topic of
• 6:43
  Speaker 1: phage therapy. But let's set the stage and remind ourselves
• 6:47
  Speaker 1: what's going on with traditional antibiotics. So, like, give us
• 6:50
  Speaker 1: the very basics. When you take penicillin or you take amoxicillin,
• 6:54
  Speaker 1: what's going on? How do those work? How do those
• 6:57
  Speaker 1: help you combat pathogens?
• 7:00
  Speaker 4: Really big question because each antibiotic is a molecule that
• 7:03
  Speaker 4: has its own type of mechanism, and so we now
• 7:06
  Speaker 4: have dozens of different kinds of antibiotics. They each work
• 7:08
  Speaker 4: in different ways. Some of them are called bacteria static,
• 7:13
  Speaker 4: so they'll halt the growth of the bacteria, they won't
• 7:15
  Speaker 4: directly kill them, and others are called bacteria cytle because
• 7:19
  Speaker 4: they can actually kill the bacteria. But the point is
• 7:22
  Speaker 4: that whichever antibiotic you're taking, the goal is that it's
• 7:25
  Speaker 4: going to prevent the bacteria from continuing to grow and
• 7:28
  Speaker 4: cause infection, and between the antibiotic and your immune system,
• 7:33
  Speaker 4: hopefully you're going to end up clearing the infection within
• 7:36
  Speaker 4: a day or two. You know, all of us have
• 7:38
  Speaker 4: probably had the experience of taking an antibiotic and feeling
• 7:41
  Speaker 4: better relatively quickly, and that's because the antibiotic is getting
• 7:46
  Speaker 4: in there, stopping or killing the bacteria, and then your
• 7:50
  Speaker 4: immune system helps clear the infection. And so we've all
• 7:53
  Speaker 4: also heard stories about how before around the era of
• 7:57
  Speaker 4: what World War two and antibiotics became more widely available,
• 8:00
  Speaker 4: people would often succumb to very normal infections that people
• 8:04
  Speaker 4: survive all the time. Right now, so we've become accustomed
• 8:07
  Speaker 4: to being able to survive infections that took people down
• 8:12
  Speaker 4: before the era of antibiotics and around the time of
• 8:15
  Speaker 4: World War two.
• 8:16
  Speaker 2: I like that. I like that a lot for bacterio
• 8:20
  Speaker 2: static stuff.
• 8:21
  Speaker 3: Is the goal here just that you are trying to
• 8:24
  Speaker 3: make sure they don't grow any more to give your
• 8:27
  Speaker 3: immune system time to kill them, or are you making
• 8:30
  Speaker 3: it so they can't reproduce and the goal is that
• 8:32
  Speaker 3: they'll die of old age at some point.
• 8:34
  Speaker 4: I think either of those would be good outcomes. So yeah, okay,
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  Speaker 4: But the point is just the population of bacteria is
• 8:41
  Speaker 4: halted in its tracks, and then your immune system has
• 8:45
  Speaker 4: a better chance to catch up.
• 8:46
  Speaker 2: Got it.
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  Speaker 1: And last time you're on the pod, you were telling
• 8:48
  Speaker 1: us about all the beneficial microbes that live within us
• 8:51
  Speaker 1: and among us. When you take one of these things,
• 8:54
  Speaker 1: are they somehow targeted towards pathogens or the things that
• 8:58
  Speaker 1: are hurting you, or is it just like an nuclear
• 9:00
  Speaker 1: bomb and it's just killing all of your microbes.
• 9:03
  Speaker 4: That's also nuanced because it depends on the antibiotic. But
• 9:07
  Speaker 4: on average, antibiotics have broader spectrum, which means that they
• 9:11
  Speaker 4: take out lots of different types of bacteria, or at
• 9:14
  Speaker 4: least a subset of bacteria, and to be honest, I'm
• 9:18
  Speaker 4: not a deep expert on exactly what each antibiotic can cover,
• 9:22
  Speaker 4: but it's definitely the case that when you take antibiotics,
• 9:26
  Speaker 4: you're likely to kill bacteria that we're not causing any
• 9:29
  Speaker 4: trouble at all. So there's there's pros and cons to that.
• 9:33
  Speaker 4: On the pro side, you don't have to think too
• 9:35
  Speaker 4: hard about which antibiotic to take. That doctor can be like, well,
• 9:38
  Speaker 4: your infection is probably kind of one of these types
• 9:41
  Speaker 4: of things, and then this antibiotic will probably take care
• 9:44
  Speaker 4: of the problem. So it's good in that sense. And
• 9:47
  Speaker 4: to be honest, at the time when we started using
• 9:49
  Speaker 4: antibiotics in the mid twentieth century, we didn't really appreciate
• 9:53
  Speaker 4: our microbiomes. We thought it'd be great if we could
• 9:55
  Speaker 4: just all be sterile, so it was kind of viewed
• 9:57
  Speaker 4: as a positive, like, yeah, just get rid of all
• 9:59
  Speaker 4: that stuff that's only causing trouble. And now we actually
• 10:02
  Speaker 4: have more nuanced appreciation for the fact that we don't
• 10:05
  Speaker 4: want to be decimating our microbes all the time. So
• 10:08
  Speaker 4: now it's we kind of appreciate that you don't necessarily
• 10:11
  Speaker 4: want these broader spectrum antibiotics taking everything out, and some
• 10:15
  Speaker 4: are a little bit more targeted than others.
• 10:17
  Speaker 3: Totally okay if this question is too far afield and
• 10:20
  Speaker 3: you want to shoot it down, but could we give
• 10:22
  Speaker 3: an example of how one kind of antibiotic focuses in
• 10:27
  Speaker 3: on one kind of bacteria or a group of closely
• 10:29
  Speaker 3: related bacteria. I think that's pretty interesting. I guess I
• 10:32
  Speaker 3: had mostly thought that when you take an antibiotic, you're
• 10:34
  Speaker 3: probably wiping out just about everything. How do you get
• 10:37
  Speaker 3: certain kinds of bacteria targeted?
• 10:40
  Speaker 4: Some molecules are focused on certain subsets of bacteria. I mean,
• 10:44
  Speaker 4: for example, tobramycin is a recently developed antibiotic that people
• 10:49
  Speaker 4: as cystic fibrosis used to treat pseudomonous infections in their lungs,
• 10:54
  Speaker 4: and so that has relatively targeted action, but of course
• 10:58
  Speaker 4: it can still understanding is that it can still kill
• 11:02
  Speaker 4: other gram negative bacteria. There's a few big categories of bacteria,
• 11:06
  Speaker 4: and some antibiotics target broadly those categories. So if you
• 11:10
  Speaker 4: to have a gram negative targeting antibiotic, then your gram
• 11:12
  Speaker 4: positives will be protected. For example, and I know there's
• 11:16
  Speaker 4: certain antibiotics that are used when you're trying to target
• 11:19
  Speaker 4: the anaerobes, which have different metabolisms. So a mira penem,
• 11:23
  Speaker 4: for example, is something I hear doctors saying they're using
• 11:26
  Speaker 4: to include coverage of the anaerobes. And you know, for example,
• 11:30
  Speaker 4: they've even shown that if you take antibiotics that do
• 11:33
  Speaker 4: not target the anaerobes, that can protect you in the hospital,
• 11:36
  Speaker 4: because the anaerobes are the gut bugs that are producing
• 11:39
  Speaker 4: all those healthy molecules when they digest your fiber, So
• 11:43
  Speaker 4: sparing them by using antibiotics that do not target anaerobes
• 11:47
  Speaker 4: can be protective. And then I think we did talk
• 11:50
  Speaker 4: about this last time, but if you decimate all your
• 11:53
  Speaker 4: gut microbes with antibiotics, which happens pretty frequently in the hospital,
• 11:57
  Speaker 4: then you can be susceptible to other infections like the
• 12:01
  Speaker 4: clusterradia defecal that causes recurrent diarrhea.
• 12:05
  Speaker 1: All right, So for hundreds of thousands of years, if
• 12:08
  Speaker 1: you've got an infection you scratched your leg or whatever,
• 12:12
  Speaker 1: you are at risk of dying. And then for fifty
• 12:16
  Speaker 1: golden years or so, we've had these powerful antibiotics to
• 12:19
  Speaker 1: protect ourselves and to make parents more relaxed when kids
• 12:23
  Speaker 1: are climbing on rusty playground equipment. But what's happening now,
• 12:28
  Speaker 1: Why are we hearing so much about antibiotic resistance? Why
• 12:31
  Speaker 1: are these things not working anymore?
• 12:33
  Speaker 4: Great question. Well, to be honest, every time we've started
• 12:36
  Speaker 4: using an antibiotic, within five or ten years we've found
• 12:40
  Speaker 4: bacteria that resist that antibiotic. So this is not a
• 12:43
  Speaker 4: new problem. This has been going on ever since we
• 12:46
  Speaker 4: first started using antibiotics. So during the whole second half
• 12:51
  Speaker 4: of the twentieth century, you know, we got penicillin, and
• 12:53
  Speaker 4: within a couple of years we had, you know, bugs
• 12:55
  Speaker 4: that could resist the antibiotic penicillin. But then we would
• 12:59
  Speaker 4: come up with new abiotics, and so during the second
• 13:02
  Speaker 4: half of the twentieth century, if you look at the
• 13:03
  Speaker 4: timeline of the discovery of antibiotics, you see all this
• 13:07
  Speaker 4: beautiful new stuff emerging from the pipeline of research every
• 13:11
  Speaker 4: few years. So there were always new options emerging. There's
• 13:15
  Speaker 4: a few reasons we don't really have that pipeline right now.
• 13:19
  Speaker 4: One of them is just the financial structure of the
• 13:22
  Speaker 4: way drugs are being paid for in our society. Because
• 13:26
  Speaker 4: antibiotics typically are acute treatments, and so it's not a
• 13:30
  Speaker 4: lucrative business for pharmaceutical companies to invest in the production
• 13:33
  Speaker 4: of new antibiotics, because, first of all, if we get
• 13:37
  Speaker 4: a new antibiotic, the doctors are going to conserve it
• 13:39
  Speaker 4: because they don't want new resistances to emerge. They're going
• 13:42
  Speaker 4: to be like, oh man, this is my lucky ticket.
• 13:44
  Speaker 4: I'm saving this for the moment I really really need it.
• 13:47
  Speaker 4: But that's going to be completely the opposite of the
• 13:50
  Speaker 4: profit structure you would need for a pharmaceutical company to
• 13:52
  Speaker 4: be willing to invest. So, to be honest, it's a
• 13:55
  Speaker 4: little bit of a financial reason, but we've had a
• 13:57
  Speaker 4: real slow down in the pipeline of the discovery of antibiotics.
• 14:01
  Speaker 4: There could be something to the fact that we found
• 14:04
  Speaker 4: the low hanging fruit, but the truth is, the world
• 14:07
  Speaker 4: of microbiology has so much diversity. It's hard to even
• 14:10
  Speaker 4: begin to explain how little of it we have discovered,
• 14:13
  Speaker 4: Like we haven't even started to look at ninety nine
• 14:16
  Speaker 4: percent of what's out there. So it's very impossible to
• 14:19
  Speaker 4: me to imagine that we don't have lots of options
• 14:22
  Speaker 4: out there if we were to put energy into it.
• 14:24
  Speaker 4: We just haven't really had the resources to put energy
• 14:26
  Speaker 4: into it lately. And so there's been really cool ideas
• 14:31
  Speaker 4: for alternative financial structures that could help. Like, for example,
• 14:34
  Speaker 4: there was a big meeting at the UN a couple
• 14:36
  Speaker 4: of years ago where they were talking about having a
• 14:39
  Speaker 4: subscription model where countries are pharmaceutical companies or even healthcare
• 14:43
  Speaker 4: companies could pay into a system where they could have
• 14:47
  Speaker 4: access to a certain drug with a solid rate and
• 14:50
  Speaker 4: then it didn't matter how much they actually used it,
• 14:53
  Speaker 4: So then there would be a financial structure independent of
• 14:55
  Speaker 4: the use of the drug. But I mean in comparison
• 14:58
  Speaker 4: to the Blockbuster's statins or ozembic, you know, antibiotics are
• 15:03
  Speaker 4: just never going to be as lucrative. So that's a
• 15:06
  Speaker 4: real problem. And then I guess another thing I absolutely
• 15:09
  Speaker 4: have to say is that about eighty percent of the
• 15:11
  Speaker 4: antibiotics used, at least in the United States are in
• 15:14
  Speaker 4: the context of agriculture. So while we do need to
• 15:18
  Speaker 4: reduce the human use of antibiotics, and I obviously support
• 15:22
  Speaker 4: antibiotics stewardship programs, the main way that we use antibiotics,
• 15:26
  Speaker 4: and probably where a lot of the resistances are arising,
• 15:29
  Speaker 4: is in agriculture. So that's where we could make a
• 15:32
  Speaker 4: lot of gains if we could reduce the use of
• 15:34
  Speaker 4: antibiotics and animals, which is a hard thing to do.
• 15:37
  Speaker 4: There's really cool models, like in Denmark they had to
• 15:41
  Speaker 4: disrupt the relationships between farmers and veterinarians in order to
• 15:45
  Speaker 4: stop the prescription of antibiotics, because if the farmer was
• 15:49
  Speaker 4: working with their old buddy veterinarian and asking for a prescription,
• 15:52
  Speaker 4: they would say. Yes. It was so hard to get
• 15:55
  Speaker 4: out of the social pressure of doing something you were
• 15:58
  Speaker 4: accustomed to.
• 15:59
  Speaker 1: But is this because like cows are getting scratches in
• 16:01
  Speaker 1: the need treatment or is it just like they're pumping
• 16:03
  Speaker 1: antibiotics in because it makes them grow faster.
• 16:06
  Speaker 4: Yes, exactly. Most of the antibiotics being used in animal agriculture.
• 16:10
  Speaker 4: It's because the antibiotics help the animals grow faster, which
• 16:13
  Speaker 4: in itself is actually a fascinating science question, like why
• 16:16
  Speaker 4: does it make them grow faster? Maybe it takes some
• 16:19
  Speaker 4: of the energy away from fighting infection and then you
• 16:21
  Speaker 4: can put that energy into beefing yourself up or literally.
• 16:28
  Speaker 1: Or poorking out a little bit.
• 16:29
  Speaker 3: Yeah, I was reading about tuberculosis the other day, and
• 16:35
  Speaker 3: you know, I think I said in a prior episode,
• 16:37
  Speaker 3: like oh, there's all these diseases we don't have to
• 16:39
  Speaker 3: worry about anymore, like tuberculosis. And then I started reading
• 16:41
  Speaker 3: about tuberculosis and it's a huge problem in India. And
• 16:45
  Speaker 3: there is recently a new antibiotic that for the same
• 16:48
  Speaker 3: reasons you mentioned, they've been holding back because they want to, like,
• 16:51
  Speaker 3: you know, make sure they can save it for the
• 16:52
  Speaker 3: special cases or whatever. But there's all these people who
• 16:55
  Speaker 3: need it now, but you know, they're worried about using
• 16:58
  Speaker 3: it and antibiotic resistance building up. So our audience seems
• 17:01
  Speaker 3: really interested in evolution and so we don't need to
• 17:05
  Speaker 3: get into it at like the molecular level. But could
• 17:07
  Speaker 3: you talk a little bit about like the microevolutionary process
• 17:10
  Speaker 3: that results in antibiotic resistance.
• 17:12
  Speaker 4: Yeah, definitely. In fact, I think it's kind of interesting
• 17:16
  Speaker 4: to think about. You know, just imagine a pile of bacteria, like,
• 17:20
  Speaker 4: are you thinking about the fact that there's a bunch
• 17:22
  Speaker 4: of diversity in there because each cell could be a mutant.
• 17:26
  Speaker 4: Microbes have very high mutation rates, so in any given population,
• 17:30
  Speaker 4: the standing diversity is quite high. Every time of cell copies,
• 17:35
  Speaker 4: there could be a mutation in there. So when we
• 17:38
  Speaker 4: talk about antibiotic resistance, cells emerging. Really, what that means
• 17:43
  Speaker 4: is that you put the selection pressure of the antibiotics
• 17:46
  Speaker 4: onto an existing community of bugs, and some of them
• 17:49
  Speaker 4: have intrinsic capacity to resist the antibiotic. So those cells
• 17:54
  Speaker 4: are the ones that survive when you give the antibiotics.
• 17:57
  Speaker 4: So I have a lecture slide that's in my brain
• 18:00
  Speaker 4: right now that you guys can't see. Where it's got
• 18:03
  Speaker 4: like all different colors of circles for the different cells,
• 18:05
  Speaker 4: and some of them are read for resistance, and that's
• 18:08
  Speaker 4: already like that at the beginning, before you even took
• 18:10
  Speaker 4: the antibiotic. Then when you take the antibiotics, some of
• 18:13
  Speaker 4: those cells survive. So that I think is a conceptual
• 18:16
  Speaker 4: difference between how most of my students think it happens
• 18:20
  Speaker 4: when I'm teaching about this. So, really, there's already resistance
• 18:23
  Speaker 4: in the population, and when you give antibiotics, some of
• 18:26
  Speaker 4: the mutations that are already there help the cells resist antibiotics.
• 18:31
  Speaker 4: Now how do they resist. Some of them have pumps
• 18:35
  Speaker 4: that can shoot the antibiotic out of the cell so
• 18:37
  Speaker 4: they can survive. Others have mutations in a part of
• 18:43
  Speaker 4: the cell that the antibiotic is trying to target. So
• 18:45
  Speaker 4: it's just like kaping, it doesn't do anything. In fact,
• 18:48
  Speaker 4: there's are really interesting diversity for the different types of
• 18:52
  Speaker 4: ways that cells can resist antibiotics. It's not only the
• 18:55
  Speaker 4: classics that you read about in textbooks, but overall, once
• 18:59
  Speaker 4: those trade become enriched in a community, they can start
• 19:02
  Speaker 4: to spread them to other cells nearby. You've probably heard
• 19:05
  Speaker 4: about like the spread of antibiotic resistance, and it's true
• 19:09
  Speaker 4: that bacterial cells are really good at sharing information. They
• 19:13
  Speaker 4: can put the information into little circular pieces of DNA
• 19:17
  Speaker 4: and shoot them around in the community, and then that
• 19:20
  Speaker 4: will help neighboring cells learn how to resist the antibiotics too.
• 19:24
  Speaker 4: So anyway, there's a number of different mechanisms for how
• 19:27
  Speaker 4: cells are able to resist antibiotics, and that's usually a
• 19:31
  Speaker 4: trait that already exists in the population and you're just
• 19:34
  Speaker 4: enriching for it at first.
• 19:35
  Speaker 2: That's really interesting.
• 19:36
  Speaker 3: So, like as someone who studies parasites, when we think
• 19:38
  Speaker 3: about resistance to drugs for parasites, you get, you know,
• 19:41
  Speaker 3: like the hookworm that randomly is able for whatever reason,
• 19:45
  Speaker 3: to resist the medication that you put in there, and
• 19:47
  Speaker 3: then they produce eggs that pass with the environment, and
• 19:49
  Speaker 3: then more people get infected by this resistant to medication hookworm.
• 19:53
  Speaker 3: But bacteria have the additional ability to be able to
• 19:57
  Speaker 3: share the traits for resistance between them, which speeds up
• 20:02
  Speaker 3: the rate of resistance moving through the population. Is it
• 20:04
  Speaker 3: would that be fair to say, yeah, ah, bacteria are tricky.
• 20:08
  Speaker 4: Definitely, Yeah, big time. They're very tricky. Yeah. And sometimes
• 20:14
  Speaker 4: the trait for resisting antibiotics comes at a cost, And
• 20:18
  Speaker 4: so if you take the pressure off and the antibiotics
• 20:21
  Speaker 4: aren't there anymore, they'll lose that trait. But it's interesting
• 20:25
  Speaker 4: sometimes the same pressures like antibiotics that help the traits
• 20:30
  Speaker 4: stay in place can come from other sources, like in
• 20:33
  Speaker 4: a wastewater treatment plant for example. There well, there might
• 20:36
  Speaker 4: actually be some antibiotics around, but there also might be
• 20:38
  Speaker 4: like heavy metals or pesticides or other kind of intense
• 20:42
  Speaker 4: molecules that sometimes the traits that the bacteria need to
• 20:45
  Speaker 4: survive antibiotics can also help them survive other situations. So
• 20:50
  Speaker 4: there's a lot of situations in our modern world that
• 20:53
  Speaker 4: push bacteria towards having these traits that help them resist
• 20:57
  Speaker 4: antibiotics direct.
• 20:58
  Speaker 1: I think there's a major misconception and that I think
• 21:00
  Speaker 1: you really helped untangle a little bit there, which is
• 21:04
  Speaker 1: that the traits are already there. It's not like the
• 21:07
  Speaker 1: community is seeing this attack and thinking, what can we
• 21:10
  Speaker 1: do to defend against this, let's brainstorm and come up
• 21:12
  Speaker 1: with something. It's just selecting for the folks that already
• 21:16
  Speaker 1: have or the bugs that already have these traits exactly.
• 21:19
  Speaker 4: Yeah, I watched that light bulb go off in my
• 21:21
  Speaker 4: classrooms my whole life, where I think a lot of
• 21:24
  Speaker 4: students imagine that you add the antibiotic and then all
• 21:27
  Speaker 4: of a sudden the bacteria start mutating in this crazy
• 21:30
  Speaker 4: new way and then they have this crazy new trait
• 21:32
  Speaker 4: or something. But it's interesting, like it's usually already there.
• 21:35
  Speaker 4: It just becomes enriched. And of course it can get
• 21:37
  Speaker 4: passed around too.
• 21:38
  Speaker 1: And what kind of infections typically cause trouble? Are there
• 21:42
  Speaker 1: some kinds that are more likely to have bacteria.
• 21:45
  Speaker 4: That are resistant, Yes, definitely. In fact, there's even an
• 21:48
  Speaker 4: acronym that the global health organizations are constantly talking about.
• 21:53
  Speaker 4: It's called the escape pathogens, which stands for enter caucus Staphylococcus,
• 21:58
  Speaker 4: club Ciela, Acinitobacter, Pseudomonas enterobacter. And sometimes we say escape
• 22:05
  Speaker 4: to add eqalie.
• 22:06
  Speaker 3: I mean, I would have guessed. I would have guessed
• 22:08
  Speaker 3: that's what that Acroym meant.
• 22:10
  Speaker 1: I totally have all those in the top of my head. Also,
• 22:14
  Speaker 1: let's just hope you don't put those into a salad dressing.
• 22:16
  Speaker 1: It sounded like a recipe.
• 22:17
  Speaker 4: Oh my gosh.
• 22:18
  Speaker 1: Yeah.
• 22:18
  Speaker 4: And there's other bugs that are not on that list
• 22:21
  Speaker 4: that do cause a lot of trouble that I work
• 22:23
  Speaker 4: on in my lab. For example, like a lot of
• 22:25
  Speaker 4: people with cancer and cystic fibrosis get lung infections from
• 22:30
  Speaker 4: a bug called Stina tripomonas, also berkel darrhea. Those are
• 22:34
  Speaker 4: gram negatives. We sometimes call them water levers. You find
• 22:37
  Speaker 4: them in tap water, Like, they can live in tap water,
• 22:39
  Speaker 4: isn't that amazing? And they can live in soil, so
• 22:42
  Speaker 4: they're You're often exposed to them in water or outside,
• 22:47
  Speaker 4: and if your immune system is compromised, they can cause
• 22:49
  Speaker 4: a lot of trouble.
• 22:50
  Speaker 1: Sorry, why is it amazing they can live in tap water?
• 22:53
  Speaker 1: I can live in tap water?
• 22:55
  Speaker 4: How long? Though? I mean you could. It's true. Water
• 22:57
  Speaker 4: will sustain a human for like a little while, but
• 22:59
  Speaker 4: at some point you're gonna need some calories and.
• 23:01
  Speaker 2: You're gonna get pruney.
• 23:02
  Speaker 1: Oh mean they can eat tap water like that's their
• 23:05
  Speaker 1: only source of calories. That's amazing.
• 23:07
  Speaker 4: I see, okay, exactly, Wow, that is amazing. Like, if
• 23:10
  Speaker 4: you pick up a bottle of water at the store,
• 23:13
  Speaker 4: it probably has some of those cells in there. And
• 23:15
  Speaker 4: I don't mean to make people not want to drink water,
• 23:18
  Speaker 4: because when I hear that there's microbs in something that
• 23:20
  Speaker 4: doesn't creep me out, I'm just like, oh cool, I'm
• 23:23
  Speaker 4: happily you know, living among them. So I'm not saying
• 23:27
  Speaker 4: you shouldn't drink water, but it's probably true that bottled
• 23:31
  Speaker 4: water has higher microbial load from those gram negatives compared
• 23:35
  Speaker 4: to like even tap water.
• 23:37
  Speaker 3: So when we say these infections cause trouble, do we
• 23:40
  Speaker 3: mean that they are bad for humans? Or do we
• 23:42
  Speaker 3: mean that they're more likely to be resistant to antibiotics?
• 23:45
  Speaker 4: Those are well, the list I just gave you are
• 23:48
  Speaker 4: of common infections that are frequently becoming resistant to antibiotics
• 23:54
  Speaker 4: in a way that's untreatable. So for each of them,
• 23:57
  Speaker 4: there's your annual statistics being compiled on a global level
• 24:01
  Speaker 4: to talk about how many infections are caused each year
• 24:04
  Speaker 4: and how many of them resist antibiotics. Sometimes meaning you
• 24:09
  Speaker 4: just have to switch antibiotics a few times, but eventually
• 24:11
  Speaker 4: you find one that works, and sometimes meaning that you
• 24:14
  Speaker 4: like literally never find an antibiotic that works. And so
• 24:17
  Speaker 4: there are a lot of people in the world right
• 24:19
  Speaker 4: now who have chronic infections that they cannot clear, like
• 24:23
  Speaker 4: from urinary tract infections are a really really big one.
• 24:28
  Speaker 4: Sometimes lung infections. Wound infections can last forever and just
• 24:32
  Speaker 4: be very very hard to treat. And they're hard to
• 24:35
  Speaker 4: get the medicine too as well, because there's poor circulation
• 24:38
  Speaker 4: in wounds. So I hear your question, and I guess
• 24:42
  Speaker 4: the answer is both. Those are bugs that through human
• 24:45
  Speaker 4: history have always caused a lot of infections. Many of
• 24:49
  Speaker 4: them are bugs that are normal parts of our microbiome
• 24:53
  Speaker 4: under good circumstances. But if your immune barriers break down,
• 24:58
  Speaker 4: which can even just mean a scrap on your skin,
• 25:00
  Speaker 4: like you could be a healthy person who just gets
• 25:02
  Speaker 4: a scratch, and then all of a sudden, staff that
• 25:04
  Speaker 4: was happily living in normal amounts on your skin can
• 25:08
  Speaker 4: then cause a terrible infection.
• 25:11
  Speaker 3: Well, I've discovered a new thing to fixate on tonight.
• 25:14
  Speaker 3: That's what's gonna keep me up. Let's take a break,
• 25:16
  Speaker 3: and when we get back, we'll talk about harnessing viruses
• 25:20
  Speaker 3: to try to kill bacteria now that antibiotics aren't really
• 25:23
  Speaker 3: doing the job.
• 25:46
  Speaker 1: Okay, we're back, and Kelly is covering herself with bubble
• 25:49
  Speaker 1: wrap to protect herself from the future of infections.
• 25:55
  Speaker 2: I can't imagine a chronic uti. That sounds awful.
• 25:58
  Speaker 4: It does sound awful, doesn't it.
• 26:00
  Speaker 1: Kachina has a salad dressing that'll fix that for you.
• 26:02
  Speaker 3: Oh my gosh, Oh that's great, that's great, or cranberry
• 26:05
  Speaker 3: pills or something. But anyway, all right, so we talked
• 26:08
  Speaker 3: about how antibiotics are not working anymore in a lot
• 26:11
  Speaker 3: of cases, and so you work on phage therapies.
• 26:14
  Speaker 2: So what is a phage.
• 26:17
  Speaker 4: Phages are viruses that kill bacteria. And so, just to
• 26:21
  Speaker 4: back up, for every cell that we have on the planet,
• 26:25
  Speaker 4: there's usually about ten kinds of viruses that can infect it.
• 26:28
  Speaker 4: So there's always viruses around that can infect every kind
• 26:31
  Speaker 4: of cell. Like that pepper or tomato on your plate,
• 26:35
  Speaker 4: there's tons of viruses that can infect that. So similarly,
• 26:38
  Speaker 4: for all of the bacteria that we've talked about, there's
• 26:41
  Speaker 4: usually about ten viruses or so that can infect that
• 26:46
  Speaker 4: cell type. So the idea of phage therapy is to
• 26:49
  Speaker 4: take the viruses that can infect bacteria and use them
• 26:54
  Speaker 4: as a medicine, kind of like the enemy of my
• 26:56
  Speaker 4: enemy is my friend.
• 26:57
  Speaker 2: Do the viruses have viruses?
• 26:59
  Speaker 4: Yeah, while there's actually yet maybe they do. Actually there's
• 27:03
  Speaker 4: kind of little hitchhiker DNA pieces that could be considered
• 27:07
  Speaker 4: viruses on viruses. So yeah, it never ends.
• 27:10
  Speaker 1: Okay, And should we think of these viruses the way
• 27:13
  Speaker 1: we think of our microbial community, like are they sometimes
• 27:16
  Speaker 1: helping the bacteria sometimes it's not so clear, sometimes hurting them?
• 27:20
  Speaker 1: Or are they're always invading and taking over? Is there
• 27:22
  Speaker 1: always a negative relationship between the viruses and the bacteria.
• 27:25
  Speaker 4: It's definitely not always negative. And I think one of
• 27:28
  Speaker 4: the big lessons of the last few years of our
• 27:31
  Speaker 4: field is that it's pretty hard to categorize them. There's
• 27:34
  Speaker 4: more of a gradient, so there's sometimes very direct killing
• 27:38
  Speaker 4: types of relationships, but there's also a lot of kind
• 27:41
  Speaker 4: of infect and hang out for a long time kind
• 27:44
  Speaker 4: of relationships. And the truth is there is no bacterial
• 27:47
  Speaker 4: community in the world that doesn't have viruses in it,
• 27:49
  Speaker 4: So we can't really talk about what it would mean
• 27:52
  Speaker 4: to be a bacterial community without viruses. They're just part
• 27:55
  Speaker 4: of the situation.
• 27:56
  Speaker 1: You know, viruses are here to stay, you're saying.
• 27:58
  Speaker 4: They're here to say, and they are a big part
• 28:00
  Speaker 4: of how bacteria work. I mean, anytime a bacterial community
• 28:04
  Speaker 4: experiences some kind of stress, they're going to be enriched
• 28:08
  Speaker 4: for the cells that can handle the stress, and viruses
• 28:10
  Speaker 4: are going to be transmitting the information to help them
• 28:13
  Speaker 4: do that. So a big part of how bacteria can
• 28:16
  Speaker 4: adapt to new situations is that the viruses help them
• 28:19
  Speaker 4: out by transmitting information.
• 28:21
  Speaker 1: I don't know how to feel about this. At first,
• 28:23
  Speaker 1: I was like, bacteria are pathogen, They're hurting us, they're
• 28:26
  Speaker 1: killing people, they're painful. UTI is now you're talking about
• 28:28
  Speaker 1: them experiencing stress, and I'm like sympathetic towards them, and
• 28:32
  Speaker 1: so like, what am I supposed to feel about bacteria, Patrina?
• 28:35
  Speaker 4: I mean, most bacteria are not pathogens, like by far,
• 28:38
  Speaker 4: Like I just named a couple bacteria that cause infections,
• 28:41
  Speaker 4: which actually are usually healthy, normal parts of our communities,
• 28:46
  Speaker 4: And then that doesn't even begin to talk about all
• 28:49
  Speaker 4: the microbes in the world. Very fewer pathogens. It's just
• 28:51
  Speaker 4: the ones on the news are pathogens. They should write
• 28:55
  Speaker 4: more positive stories about helpful microbes should.
• 28:59
  Speaker 3: I do see a lot of them, although they're not
• 29:01
  Speaker 3: very good scientifically, but always But okay, So if every
• 29:05
  Speaker 3: bacteria has ten viruses, does that mean that viruses are
• 29:09
  Speaker 3: the most like diverse and specios life on the planet
• 29:14
  Speaker 3: or is are the same viruses infecting lots of different
• 29:17
  Speaker 3: kinds of bacteria?
• 29:18
  Speaker 4: They are by far the most diverse. That is exactly
• 29:22
  Speaker 4: the thing to say. I mean, I've got all like,
• 29:24
  Speaker 4: there's so many cool analogies. There's more viruses than stars
• 29:29
  Speaker 4: in the galaxy or grains of sand on the planets.
• 29:32
  Speaker 4: I think it's ten to the thirty one. If you
• 29:34
  Speaker 4: line them up head to head, they go to the
• 29:36
  Speaker 4: edge of the galaxy back and forth a bunch of times.
• 29:39
  Speaker 4: You know, it's a crazy number of viruses. Yes, they
• 29:41
  Speaker 4: are super super diverse, and you asked a really important
• 29:46
  Speaker 4: question about how specific they are. Like, is a virus
• 29:49
  Speaker 4: that infects one of those bugs, the pseudomonis also able
• 29:53
  Speaker 4: to infect a different bug that staphylococcus or something like that.
• 29:56
  Speaker 4: Typically know, in fact, it's at a substrain level. A
• 30:00
  Speaker 4: phage that infects one pseudomonis. It's it's like a sub
• 30:04
  Speaker 4: type of pseudomonis, Like like any type of bacteria has
• 30:09
  Speaker 4: genus and species names. You know, King's play chests on
• 30:12
  Speaker 4: fine grain sand. The taxonomy going down to genus and species.
• 30:15
  Speaker 2: Oh, you learned a nice one.
• 30:18
  Speaker 4: Yeah, there's probably less of for a free ones going
• 30:20
  Speaker 4: around the schoolyard.
• 30:21
  Speaker 2: Yea, I won't repeat mine.
• 30:23
  Speaker 4: Go ahead, And so there's even substrains, So like Pseudomonius
• 30:27
  Speaker 4: originosa is a genus and species name, but there's subtypes
• 30:32
  Speaker 4: beyond that, and whether the phage infects is usually at
• 30:37
  Speaker 4: a sub type level like that, and it's kind of
• 30:39
  Speaker 4: interesting to think about it. I mean, the bacteria are
• 30:42
  Speaker 4: constantly making small mutations to resist the phages, so the
• 30:47
  Speaker 4: trait of resisting a phage turns on a dime. It's
• 30:50
  Speaker 4: just one mutation can probably do the trick, so it's
• 30:54
  Speaker 4: not like a big complicated trait like using oxygen and
• 30:58
  Speaker 4: then you would need like a whole bunch of different
• 31:00
  Speaker 4: and it's like very conserved, and if you looked back
• 31:02
  Speaker 4: in the history of bacteria, you'd see big movement towards like, oh,
• 31:07
  Speaker 4: now they can use oxygen or something like that. Phage
• 31:10
  Speaker 4: infection is like a tiny little thing. It's very easy
• 31:12
  Speaker 4: to change it. It's at the tippy tippy branches of
• 31:14
  Speaker 4: the toxinomic trees.
• 31:16
  Speaker 1: And so if there are all these viruses out there
• 31:18
  Speaker 1: that are infecting bacteria, and they're very specific to the bacteria,
• 31:22
  Speaker 1: but a very small change in the bacteria could mean
• 31:25
  Speaker 1: that they can't be infected by the viruses. Is there
• 31:27
  Speaker 1: some vast ocean of viruses out there that can't infect
• 31:30
  Speaker 1: any bacteria yet and some mutation of the bacteria makes
• 31:33
  Speaker 1: them therefore susceptible or do viruses only exist and propagate
• 31:38
  Speaker 1: if they can use bacteria.
• 31:39
  Speaker 4: Well, I think there is an ocean of viruses out
• 31:43
  Speaker 4: there that never get to infect a cell. So they
• 31:45
  Speaker 4: have kind of an unrequited dream of finding a host
• 31:49
  Speaker 4: and they just never do. However, the dark virus, the
• 31:53
  Speaker 4: lonely ones.
• 31:55
  Speaker 1: But now you're making a sympathetic to viruses, Katrina, You
• 31:58
  Speaker 1: are too empathetic.
• 32:00
  Speaker 4: But so, yes, there's going to be viruses out there
• 32:03
  Speaker 4: that never get to infect a sell. But the strategy
• 32:07
  Speaker 4: of a virus is to make a bajillion copies with
• 32:11
  Speaker 4: lots of variation and hope that you know several of
• 32:14
  Speaker 4: them have the capacity to go and find a host
• 32:18
  Speaker 4: in a changing world. You know. It's like and rather
• 32:21
  Speaker 4: than training one kid with lots of skills and hoping
• 32:24
  Speaker 4: they'll find a job in a changing world, it's like,
• 32:26
  Speaker 4: you got to raise billions of viruses and a few
• 32:30
  Speaker 4: of them will continue to be able to infect. And
• 32:33
  Speaker 4: I mean it's been going on for a long time,
• 32:35
  Speaker 4: and in a way it's quite stable. Like if I
• 32:37
  Speaker 4: took samples from anybody listening to this podcast right now,
• 32:42
  Speaker 4: and then in five more years took another sample, most
• 32:46
  Speaker 4: of the gut viruses would still be there. They might
• 32:50
  Speaker 4: have evolved, even one to three percent of their genome
• 32:53
  Speaker 4: could have changed in a new direction, but I would
• 32:56
  Speaker 4: be able to recognize them as themselves. So it's not
• 32:59
  Speaker 4: like it's this raucous thing that's turning over and becoming
• 33:02
  Speaker 4: a totally different thing all the time. There's some stability there,
• 33:06
  Speaker 4: especially within the individual. Just each of our guts is
• 33:09
  Speaker 4: like a little chemostat with tons of virus and bacterial
• 33:12
  Speaker 4: evolution happening all the time, and it drifts around a bit,
• 33:16
  Speaker 4: but it's it's quite stable in some ways.
• 33:19
  Speaker 1: So we are the interlopers, the weird ones in a viral.
• 33:22
  Speaker 4: World, Right, That's certainly one way of looking at it.
• 33:24
  Speaker 4: I mean, I think we have some advantages. I think
• 33:28
  Speaker 4: consciousness does have a does distinguish us from viruses.
• 33:34
  Speaker 2: There's days when I'd rather not have consciousness.
• 33:37
  Speaker 3: But anyway, Okay, so we've got viruses and some of
• 33:40
  Speaker 3: them are bad for bacteria. How do we harness that
• 33:44
  Speaker 3: to fight bacteria?
• 33:46
  Speaker 4: So basically, the way that phage therapy has worked since
• 33:50
  Speaker 4: even before we had antibiotics, So we've been doing this.
• 33:53
  Speaker 4: Phages were discovered in nineteen fifteen or nineteen seventeen, depending
• 33:57
  Speaker 4: how you look at it. And what we do is
• 34:01
  Speaker 4: if you have a bacteria causing an infection, you use
• 34:05
  Speaker 4: that as a hook and you go hunt for phages
• 34:08
  Speaker 4: in a sample that has a lot of microbial activity
• 34:11
  Speaker 4: to it. Wastewater is a popular place to hunt, but
• 34:15
  Speaker 4: freshwater ponds, puddles in front of your building.
• 34:19
  Speaker 1: Wastewater is such a euphemism. I mean, you're talking about
• 34:22
  Speaker 1: poop to pills, right, We're like finding medicine in sewage.
• 34:26
  Speaker 4: Sewage is such a concentrated way to grab the microbes
• 34:31
  Speaker 4: of humanity that it's a very tempting place to look. Yes,
• 34:34
  Speaker 4: because it's going to represent, it's going to represent a
• 34:37
  Speaker 4: lot of people. Like when we were doing our wastewater
• 34:39
  Speaker 4: sequencing project during the pandemic, we were getting eight samples
• 34:43
  Speaker 4: per week from southern California wastewater treatment plants that represented
• 34:46
  Speaker 4: sixteen million people. Wow, from just eight samples.
• 34:50
  Speaker 2: You are the queen of silver linings.
• 34:53
  Speaker 1: Sewage is so tempting, said nobody.
• 34:55
  Speaker 5: Ever.
• 34:56
  Speaker 1: Anyway, maybe we're not going to put you charge of
• 35:00
  Speaker 1: marketing and flavors for the new cell addressing company. So
• 35:05
  Speaker 1: you're saying you have a bacteria you're looking to target.
• 35:07
  Speaker 1: Then you go out and you search extent of communities
• 35:11
  Speaker 1: of viruses and you're trying to find one that will
• 35:14
  Speaker 1: kill this particular bacteria exactly.
• 35:16
  Speaker 4: So you take the infecting cells, you mix them with
• 35:21
  Speaker 4: some wastewater, and then we use a technique. I mean,
• 35:26
  Speaker 4: I need slides. Man, This is hard on a podcast, but.
• 35:29
  Speaker 2: I don't want to show you guys pictures it is.
• 35:31
  Speaker 4: But you know, you make a plate of the bacteria
• 35:35
  Speaker 4: mixed with the material that you hope has phages in it.
• 35:39
  Speaker 4: And an important thing to say is that we filter it.
• 35:41
  Speaker 4: We try to get the cells out of there. So
• 35:43
  Speaker 4: it's just viruses left behind, because otherwise you might imagine
• 35:46
  Speaker 4: everything from the whole wastewater treatment plant growing on your plate.
• 35:49
  Speaker 4: But actually you filter and hopefully there's viruses in there
• 35:52
  Speaker 4: that infect your cell. But it's a mystery every time.
• 35:55
  Speaker 4: Sometimes we spend six months hunting for a phage for
• 35:58
  Speaker 4: one strain, even though I've got like really good people
• 36:01
  Speaker 4: with lots of experience, and I've got tons of great wastewater.
• 36:04
  Speaker 4: I'll tell you that.
• 36:06
  Speaker 1: So it's sort of like you have a lock and
• 36:08
  Speaker 1: you're putting it in a bag of keys and shaking
• 36:10
  Speaker 1: it around and hoping and one of them goes in.
• 36:12
  Speaker 4: Yeah, And then then you get more experience with knowing
• 36:15
  Speaker 4: what kinds of wastewater treatment plants are enriched for the
• 36:18
  Speaker 4: bugs you care about. Like for Ourstina tri Promona's project,
• 36:22
  Speaker 4: the wastewater in Escondido is like amazingly good. So if
• 36:25
  Speaker 4: I get astino infection, I'm like telling the students, please
• 36:28
  Speaker 4: get the Escondido wastewater.
• 36:30
  Speaker 1: What are they eating in Escondido or.
• 36:32
  Speaker 4: Is it because of like an agricultural influence or I
• 36:34
  Speaker 4: don't know. I would love to know the answer to that,
• 36:36
  Speaker 4: but I can tell you it's been true for years
• 36:38
  Speaker 4: and lots of other labs failed to find Stina Tripromona's phages.
• 36:42
  Speaker 4: But when we use Escondido wastewater. We've even sent our
• 36:44
  Speaker 4: Escondido wastewater to collaborating labs and they've also succeeded.
• 36:49
  Speaker 1: It's liquid gold.
• 36:50
  Speaker 4: Yeah. So then once you if you're lucky, and you'll
• 36:53
  Speaker 4: come in in the morning and you'll see a white
• 36:55
  Speaker 4: bacterial lawn, and then you'll see these clearance zones on
• 36:58
  Speaker 4: the plate. Those represent the phages. So if you get
• 37:02
  Speaker 4: one of those, then you have a manufacturing project on
• 37:05
  Speaker 4: your hands. Then you have to get the phage into
• 37:07
  Speaker 4: big enough amounts and clean enough amounts.
• 37:10
  Speaker 1: Right back up and explain what you were talking about.
• 37:12
  Speaker 1: There a white bacterial.
• 37:14
  Speaker 4: Lawn, so you'll have a plate of bacteria that look white.
• 37:19
  Speaker 4: So you'll have like a flat white background.
• 37:21
  Speaker 1: Why do they look white.
• 37:22
  Speaker 4: Well, some bacteria are a little bit yellow, or most
• 37:25
  Speaker 4: bacteria are white or yellow. Sometimes they turn a little blue.
• 37:28
  Speaker 4: But the point is you have a clear growth of
• 37:32
  Speaker 4: cells on your plate. And then you can see with
• 37:35
  Speaker 4: your naked eye that there are clearance zones from the
• 37:38
  Speaker 4: viruses and so that represents if one virus infects one
• 37:42
  Speaker 4: of the cells on that plate, it will keep replicating
• 37:45
  Speaker 4: and chewing up and eating and breaking the cells, so
• 37:49
  Speaker 4: you'll get a clearance zone that's visible to the naked eye.
• 37:51
  Speaker 4: I mean, obviously one virus is not visible to the
• 37:53
  Speaker 4: naked eye. But what is visible to the naked eye
• 37:56
  Speaker 4: is it's called a plaque, and it's a bunch of
• 37:59
  Speaker 4: cell death caused by the virus in one little zone
• 38:03
  Speaker 4: of the plate. And you can see that.
• 38:05
  Speaker 1: And how do you know which virus has done it?
• 38:07
  Speaker 4: You don't. You just know it looks like a virus.
• 38:10
  Speaker 4: And if you've done it for a long time, you
• 38:12
  Speaker 4: start to get familiar with the way the shape and
• 38:15
  Speaker 4: the size of the of the plaque the clearance zone.
• 38:19
  Speaker 4: You can usually distinguish it from an air bubble or
• 38:22
  Speaker 4: something like that, but not always. So it's definitely still
• 38:25
  Speaker 4: an identification project once you get the plaque. But that's
• 38:29
  Speaker 4: kind of step one. So really, in my lab, if
• 38:32
  Speaker 4: someone sends us every week or two, we get a
• 38:35
  Speaker 4: new isolate into our lab where a doctor has a
• 38:38
  Speaker 4: patient who has antibiotic resistant infection and they want to
• 38:41
  Speaker 4: know do we have a phage. So the first thing
• 38:44
  Speaker 4: we do is we reach into our freezer, which where
• 38:46
  Speaker 4: we already have about two hundred phages, and then we'll
• 38:49
  Speaker 4: see if one of the ones that infected a similar
• 38:52
  Speaker 4: strain can infect this new one. That's the easiest answer,
• 38:56
  Speaker 4: because then we'll have already sequenced it, we'll know what
• 38:58
  Speaker 4: it is. It's a big head start, but it's not uncommon.
• 39:02
  Speaker 4: I'd say easily half the time that none of the
• 39:04
  Speaker 4: phages we have can infect. So then we do a
• 39:07
  Speaker 4: new hunt in wastewater.
• 39:09
  Speaker 1: And you have like your own personal lab library, like
• 39:12
  Speaker 1: the ones you're talking about in your freezer. There's another
• 39:14
  Speaker 1: lab somewhere else to have a different set. Yeah, another
• 39:16
  Speaker 1: lab has a different set. This is like Katrina's personal
• 39:19
  Speaker 1: phage arsenal.
• 39:20
  Speaker 4: That's right, Yeah, And it's the way that you protect
• 39:23
  Speaker 4: the information is really complicated, and we're all everyone's always
• 39:26
  Speaker 4: changing their mind about that. My general attitude has been
• 39:29
  Speaker 4: to be very open and if somebody at another university
• 39:31
  Speaker 4: needs one of our phages, I just send it to them.
• 39:34
  Speaker 4: But we could be shooting ourselves as a community all
• 39:37
  Speaker 4: in the foot because we're removing the capacity to make
• 39:40
  Speaker 4: money off of them, so then nobody would ever invest
• 39:43
  Speaker 4: in what we need is for like real investment to
• 39:45
  Speaker 4: get this thing off the ground, you know, all right.
• 39:48
  Speaker 1: So back on the process. Here, you have the isolate.
• 39:50
  Speaker 1: You scan through all your phages by just like mixing
• 39:52
  Speaker 1: them together and seeing if one of them kills your bacteria.
• 39:55
  Speaker 1: Maybe you have to go out to Escondido or somewhere
• 39:57
  Speaker 1: else to find more phages. But now you have one
• 40:00
  Speaker 1: that you think kills the bacteria, what do you do next?
• 40:03
  Speaker 4: Then we purify. We have to like continue propagating and purifying.
• 40:09
  Speaker 4: Most phage preps are contaminated in some way. It's actually
• 40:12
  Speaker 4: very hard to get a prep that has just a
• 40:14
  Speaker 4: single phage in it because they come out of these
• 40:16
  Speaker 4: communities with a lot of different members. So step one
• 40:20
  Speaker 4: is propagating, where you pick the plaque and you reinfect bacteria,
• 40:25
  Speaker 4: and it's like a twenty four hour project each time.
• 40:29
  Speaker 4: And you do that easily, like three or four times,
• 40:33
  Speaker 4: and some phages will kind of peter out at that
• 40:35
  Speaker 4: point and reveal themselves to be hard to work with.
• 40:38
  Speaker 4: And so if you have multiple different types emerging on
• 40:41
  Speaker 4: your plate, you just abandon the ones that are difficult
• 40:44
  Speaker 4: to deal with, because what you want are easy to
• 40:46
  Speaker 4: deal with.
• 40:46
  Speaker 1: Phages difficult to deal with. Like they send grumpy emails
• 40:49
  Speaker 1: late at night or what's going on.
• 40:51
  Speaker 4: Like they one day they make a beautiful plaque, and
• 40:54
  Speaker 4: then the next day, even though you did everything exactly
• 40:57
  Speaker 4: the same way, as far as you know, it just
• 40:58
  Speaker 4: doesn't do anything. And you're like going back to the
• 41:01
  Speaker 4: plate from two days ago and hoping you can get
• 41:03
  Speaker 4: it to cooperate again. That kind of thing.
• 41:06
  Speaker 3: It's biology, So it depends, yes, And by a beautiful plaque,
• 41:09
  Speaker 3: you mean like one day it beats the heck out
• 41:11
  Speaker 3: of the bacteria, and the next day it doesn't seem
• 41:13
  Speaker 3: to kill them at all.
• 41:14
  Speaker 4: Yeah, Like maybe you'll get a nice, big, visible plaque,
• 41:17
  Speaker 4: which means it's easy to pick so you can get
• 41:20
  Speaker 4: material to work with for the next day. And then
• 41:22
  Speaker 4: the next day your plate has nothing on it, so
• 41:25
  Speaker 4: you're like, where did it even go?
• 41:26
  Speaker 3: So each time you're picking the viruses that killed the
• 41:29
  Speaker 3: bacteria and putting them onto a new plate exactly and
• 41:31
  Speaker 3: hoping to get a pure culture eventually.
• 41:33
  Speaker 4: Exactly, and then then you find out all these finicky
• 41:36
  Speaker 4: things about how to deal with them. Some viruses prefer
• 41:39
  Speaker 4: to grow in liquid, others prefer to grow on a
• 41:42
  Speaker 4: solid plate. Others do really well, when the cells are
• 41:46
  Speaker 4: multiplying quickly, others do better when the cells are like
• 41:50
  Speaker 4: kind of overnight growths that got tired out, and we
• 41:54
  Speaker 4: call them stationary phase. You know, they're like not as
• 41:56
  Speaker 4: actively growing anymore. And viruses have all different mechanism as
• 42:00
  Speaker 4: of entry and preferences for metabolism. So all of those things,
• 42:04
  Speaker 4: you don't know them about your new virus yet you're
• 42:07
  Speaker 4: just like trying to propagate it. So then we'll do
• 42:10
  Speaker 4: all kinds of things where we'll do temperature gradients and
• 42:14
  Speaker 4: different types of media growth, and we'll try like triangulating
• 42:18
  Speaker 4: all the conditions to learn what this particular virus likes
• 42:22
  Speaker 4: the best, so then we can do a better job
• 42:24
  Speaker 4: of propagating it in successful conditions.
• 42:26
  Speaker 3: All Right, So we've learned how to make a virus happy,
• 42:28
  Speaker 3: and when we get back, we'll talk about actually giving
• 42:31
  Speaker 3: those viruses to people.
• 42:52
  Speaker 1: Okay, we're back, and we're hearing about how Katrina's lab
• 42:56
  Speaker 1: might save somebody who's out there with a really difficult
• 42:59
  Speaker 1: infection whose doctor emails her and asks her if she's
• 43:02
  Speaker 1: got something cooking up in the freezer that can kill
• 43:04
  Speaker 1: their bacteria. So we've heard about how you find a
• 43:07
  Speaker 1: fade that can help infect your bacteria, you purify, you isolated.
• 43:11
  Speaker 1: How do you actually go all the way to putting
• 43:14
  Speaker 1: it back into human and treating them.
• 43:17
  Speaker 4: Well, that's a really big question, but it's actually an
• 43:19
  Speaker 4: old question. So since around nineteen twenty, especially in the
• 43:25
  Speaker 4: former Soviet republics, phages have been used as medicine since
• 43:28
  Speaker 4: before we even had antibiotics, and they were actually used
• 43:31
  Speaker 4: in the Western world, you know, before the era of
• 43:34
  Speaker 4: World War Two as well, Like for example, when Elizabeth
• 43:38
  Speaker 4: Taylor was filming Cleopatra, I think she was in the UK,
• 43:40
  Speaker 4: she got a terrible staff infection and they used phages
• 43:43
  Speaker 4: to help clear her infection. Wow, there's a lot of
• 43:45
  Speaker 4: stories like that from around that time. And so at
• 43:49
  Speaker 4: the Eliava Institute in Tiblis, Georgia, which is probably the
• 43:53
  Speaker 4: most famous of these centers, they've been using phage therapy
• 43:58
  Speaker 4: to treat infections for more than a century and so
• 44:01
  Speaker 4: they it's the process like I just told you about.
• 44:04
  Speaker 4: They have a much bigger bank of phages than I do,
• 44:05
  Speaker 4: I'm sure, but they will find a phage. If one
• 44:08
  Speaker 4: of their standard ones doesn't work, they'll go find a
• 44:11
  Speaker 4: new one and they prep it and give it to you.
• 44:15
  Speaker 4: But in the United States, there is no approved way
• 44:19
  Speaker 4: to use phages. It's not sold. There's no FDA approved
• 44:23
  Speaker 4: medication that your doctor can prescribe. So all of it
• 44:27
  Speaker 4: is happening through labs like mine and through applications to
• 44:32
  Speaker 4: the Federal Drug Administration asking for an exemption, either as
• 44:36
  Speaker 4: an emergency authorization or as a compassionate use exemption. So
• 44:40
  Speaker 4: it has to be a situation where somebody's in really
• 44:44
  Speaker 4: dire straits and taking on the risk of an experimental
• 44:47
  Speaker 4: treatment makes sense. So in my lab, for many years,
• 44:51
  Speaker 4: I've been growing up these phages out of wastewater, and
• 44:53
  Speaker 4: people were sometimes sending me their patient's isolates and asking
• 44:56
  Speaker 4: if we had a phage, and we almost always succeeded.
• 44:59
  Speaker 4: That was not the bare, but usually the person would
• 45:02
  Speaker 4: either get better or pass away before we could get
• 45:06
  Speaker 4: the phage prepped in order to help them. And that
• 45:08
  Speaker 4: went on for years, and every time I would have
• 45:11
  Speaker 4: a student who was such a good spirit and would
• 45:14
  Speaker 4: spend the whole weekend working really hard to get the phages,
• 45:17
  Speaker 4: and we'd be so proud of the fact that we
• 45:19
  Speaker 4: had one, but then it wouldn't actually help anyone because
• 45:22
  Speaker 4: the whole process is too slow to help someone in
• 45:24
  Speaker 4: really dire straits. So about a year ago I went
• 45:28
  Speaker 4: to the Infectious Disease Department Grand Rounds at UC Irvine
• 45:31
  Speaker 4: where I work, and I talked to all the doctors
• 45:34
  Speaker 4: about it, and I got a lot of help from
• 45:36
  Speaker 4: Jessica Satcher of the Phage Directory. This was her idea,
• 45:39
  Speaker 4: I think, actually, and we talked about how we should
• 45:42
  Speaker 4: aim for people who are not quite so acutely ill,
• 45:46
  Speaker 4: people who have a more chronic infection, where their life
• 45:49
  Speaker 4: would change and be improved if we could help them,
• 45:52
  Speaker 4: but where if it took us like six months or
• 45:54
  Speaker 4: a year to get all the approvals and to prep
• 45:55
  Speaker 4: the phage, that would be okay. So that was April
• 45:59
  Speaker 4: twenty twenty five. So since then I've had ten cases.
• 46:02
  Speaker 4: We found phages in every single one, but only once
• 46:06
  Speaker 4: have we gotten all the way to the FDA approval
• 46:09
  Speaker 4: and actually give the page to a person step. And
• 46:11
  Speaker 4: it's all thanks to a student named Ritwick Kumar. You know,
• 46:15
  Speaker 4: he's really the reason this all happened. So he personally
• 46:18
  Speaker 4: found well with a team of other students and a
• 46:21
  Speaker 4: medical resident who joined our lab as a volunteer. Actually
• 46:24
  Speaker 4: Ritwick hunted for a staff phage for the patient I'm
• 46:27
  Speaker 4: talking about for about six months and never found one.
• 46:30
  Speaker 4: Then the first week our new medical resident Alexandra showed up,
• 46:34
  Speaker 4: she found a phage. So there must have been something
• 46:37
  Speaker 4: different about her technique or the patch of wastewater we
• 46:41
  Speaker 4: used that week or something. Anyway, we got a wonderful
• 46:45
  Speaker 4: staff phage. We named her Lude Miller, and Alexandra I
• 46:48
  Speaker 4: named her Lude Miller and so since last summer we
• 46:54
  Speaker 4: have been prepping this phage Ludmilla to help a patient
• 46:57
  Speaker 4: at the CI Medical Center who as a chronic sinusitis
• 47:01
  Speaker 4: with MRSA meth cylline resistant Staphylococcus aureus in their nose.
• 47:06
  Speaker 4: And the doctor felt that it was a good case
• 47:09
  Speaker 4: because the patient is getting frequent fevers and so their
• 47:14
  Speaker 4: quality of life is very affected. But they're stable enough
• 47:17
  Speaker 4: that if we took six months or a year, it
• 47:19
  Speaker 4: would be okay. And that is how long it took.
• 47:21
  Speaker 4: So I actually sent Ritwick to my friend darray Vantyne's
• 47:25
  Speaker 4: lab at pitt to learn how they prep the phages
• 47:27
  Speaker 4: because we were a little new at it and I
• 47:29
  Speaker 4: wanted to make sure that we were getting good advice
• 47:31
  Speaker 4: and he could like watch somebody else doing all the steps.
• 47:35
  Speaker 4: And then we also chose a gram positive bacteria, Staphylococcus,
• 47:40
  Speaker 4: because it doesn't carry endotoxins, which are really hard to
• 47:43
  Speaker 4: purify out of bacterial preps. So it kind of made
• 47:46
  Speaker 4: the process simpler by starting with a gram positive anyway,
• 47:49
  Speaker 4: so Ritwick made a big batch of these phages.
• 47:53
  Speaker 1: He stewed up some lud Milli soup, he.
• 47:56
  Speaker 4: Stewed up some lud Milli soup, and then he filtered
• 47:58
  Speaker 4: out all the stuff that could cause trouble. And I mean,
• 48:01
  Speaker 4: I probably should not go into so many details about
• 48:04
  Speaker 4: the protocol, but ask questions if you're interested. And so
• 48:07
  Speaker 4: we prepped up the phage in a safe way, and
• 48:10
  Speaker 4: then we actually even sent it out to a third
• 48:12
  Speaker 4: party lab to test for storility and endotoxin. And because
• 48:17
  Speaker 4: I didn't want it to be just like yeah, I mean,
• 48:18
  Speaker 4: my students think this is really clean. I wanted it
• 48:21
  Speaker 4: to be like official, you know, yeah, and that's actually
• 48:23
  Speaker 4: required by the FDA as well. And so once we
• 48:26
  Speaker 4: had all that stuff done, we made this fifty page
• 48:29
  Speaker 4: document and sent it to the FDA asking for authorization
• 48:33
  Speaker 4: to use the phage. Actually it was very interesting. Initially
• 48:36
  Speaker 4: we wanted to use the phage in an IV form,
• 48:40
  Speaker 4: and the FDA came back and suggested instead that we
• 48:43
  Speaker 4: do a sinus rinse, which I think was a really
• 48:46
  Speaker 4: smart move because there's less chance for immune reaction. I
• 48:51
  Speaker 4: don't have high expectations of problems with this, by the way,
• 48:54
  Speaker 4: I mean beyond the Eliava Institute's century of experience. Now
• 48:58
  Speaker 4: in the United States, there's been several hundred cases in
• 49:00
  Speaker 4: the last couple of years, and I'm not aware of
• 49:03
  Speaker 4: any adverse events.
• 49:04
  Speaker 3: And by that you mean nobody's had like a weird
• 49:06
  Speaker 3: immune response to getting viruses put in them, Like, yeah,
• 49:09
  Speaker 3: everybody's fine. Maybe it doesn't kill the bacteria, but it
• 49:12
  Speaker 3: doesn't hurt.
• 49:12
  Speaker 4: The people exactly. The person doesn't have a negative reaction
• 49:16
  Speaker 4: to the treatment so far. I mean, it's still experimental,
• 49:20
  Speaker 4: but so far there haven't been people having negative reactions. Great.
• 49:25
  Speaker 1: What an amazing bespoke process though, like a lab with
• 49:28
  Speaker 1: a student focused on one patient for months and months
• 49:31
  Speaker 1: and months. What a huge process and all this application
• 49:34
  Speaker 1: All right, so tell us what happens.
• 49:36
  Speaker 4: Yeah, did Ludmilla helpful? Well, I don't know yet. Yesterday.
• 49:40
  Speaker 4: It's been three weeks, so it's a six week treatment process,
• 49:45
  Speaker 4: so it's daily sinus forrinstance for six weeks. Good news,
• 49:49
  Speaker 4: nothing bad has happened, But really we won't know. I mean,
• 49:53
  Speaker 4: I think it's possible that they're feeling a little bit better,
• 49:56
  Speaker 4: but they're also getting antibiotics at the same time. So
• 49:58
  Speaker 4: the moment of truth will about three to four weeks
• 50:02
  Speaker 4: after the six weeks treatment because usually after the antibiotics
• 50:06
  Speaker 4: are stopped, the fevers come back. So we're gonna wait
• 50:09
  Speaker 4: to see if the fevers do not come back at
• 50:13
  Speaker 4: the end of the six weeks.
• 50:14
  Speaker 1: All right, Well, we're recording this episode in mid August,
• 50:17
  Speaker 1: but we're gonna post it later, so just before posts,
• 50:19
  Speaker 1: we'll get an update from Katrina on how this is going.
• 50:22
  Speaker 1: So listen at the end of the episode for a
• 50:25
  Speaker 1: more recent update from Katrina.
• 50:27
  Speaker 4: Oh what a good idea. I'm excited, but there's I mean,
• 50:29
  Speaker 4: there are actually a lot of interesting cases to follow.
• 50:32
  Speaker 4: In fact, I was at the Evergreen Phage meeting in Knoxville, Tennessee,
• 50:35
  Speaker 4: last week, and I met a man who has been
• 50:38
  Speaker 4: coming to the meeting a couple of times who had
• 50:40
  Speaker 4: a really terribly coli infection, and he actually traveled to
• 50:43
  Speaker 4: the Eliava Institute and too Blisi, Georgia, where they do
• 50:46
  Speaker 4: these phage treatments. They cooked up a specific phage just
• 50:50
  Speaker 4: for his infection because none of the ones in their
• 50:53
  Speaker 4: bank were effective, and the doctors there had him do
• 50:59
  Speaker 4: three twenty day courses of three times a day phage
• 51:02
  Speaker 4: treatment and it wasn't until the second twenty day course
• 51:07
  Speaker 4: that he started to feel better and then his bacterial
• 51:10
  Speaker 4: load and his blood dropped. So it's not necessarily that
• 51:14
  Speaker 4: you would see a big effect in the first couple weeks,
• 51:17
  Speaker 4: like in his case, at least it took several times,
• 51:19
  Speaker 4: and he wrote a book about it. He's been on
• 51:21
  Speaker 4: a lot of podcasts. It's a really really cool story.
• 51:24
  Speaker 4: So I's so cool that it worked for him. And
• 51:26
  Speaker 4: if you look at the summary of some of those
• 51:28
  Speaker 4: hundreds of cases that have been going on lately, it
• 51:30
  Speaker 4: looks like seventy five to eighty percent of people have
• 51:34
  Speaker 4: a positive responses and like their infection is helped.
• 51:37
  Speaker 2: Wow, but it's still.
• 51:39
  Speaker 4: Very early days. I mean, as you say, Daniel, it's
• 51:41
  Speaker 4: like kind of crazy to imagine that there's an individual
• 51:44
  Speaker 4: lab customizing a treatment to each person. But on the
• 51:48
  Speaker 4: other hand, the skills it takes are not that crazy,
• 51:50
  Speaker 4: Like I don't understand why we wouldn't have phage therapy
• 51:53
  Speaker 4: clinics to be able to do this for people, Like
• 51:56
  Speaker 4: the resources are not that intense. Then, know how is
• 52:00
  Speaker 4: you know something that a good student can learn how
• 52:02
  Speaker 4: to do.
• 52:02
  Speaker 3: I mean, we've known about this for one hundred years.
• 52:04
  Speaker 3: There's an institute in Georgia. Why isn't it more common? Like,
• 52:08
  Speaker 3: why doesn't the US allow this to happen all the time?
• 52:11
  Speaker 4: I think it's a medical history question. I think we
• 52:15
  Speaker 4: just went down a road using antibiotics and they were
• 52:18
  Speaker 4: approved into the medical system that we have, and it's
• 52:23
  Speaker 4: a very different system. For antibiotics. There's a few dozen molecules,
• 52:27
  Speaker 4: so it's possible to approve each of one of them
• 52:30
  Speaker 4: in a trial that these days would cost one hundred
• 52:32
  Speaker 4: million dollars to get a drug through a Phase three
• 52:35
  Speaker 4: clinical trial. You can't really do that for every single phage. Obviously,
• 52:40
  Speaker 4: it's possible that the FDA will approve the preparation methods
• 52:45
  Speaker 4: that we use and then that would work for multiple
• 52:47
  Speaker 4: different kinds of phages. But using the model of clinical
• 52:50
  Speaker 4: trials that we currently have for approving drugs won't work
• 52:53
  Speaker 4: for phages because you need different ones for each infection.
• 52:57
  Speaker 4: So that's the real reason that it's not happening as
• 53:00
  Speaker 4: much right now. I would say, how do you.
• 53:02
  Speaker 1: See it scaling up? Like is there a future in
• 53:04
  Speaker 1: which people have individualized medicine where I don't need Katrina
• 53:08
  Speaker 1: and her lab like working on me individually, it's like
• 53:11
  Speaker 1: roboticized or automated, or how do we make this more
• 53:15
  Speaker 1: wide threaten?
• 53:15
  Speaker 4: It could be that we can develop, evolve or engineer
• 53:19
  Speaker 4: phages that have broader host range so that we would
• 53:22
  Speaker 4: only need a relatively small number of phages to cover
• 53:25
  Speaker 4: most common infections. So that is certainly one possibility. That's
• 53:30
  Speaker 4: a science question. I don't know if that's possible or not,
• 53:33
  Speaker 4: but like in my own lab, we often do experiments
• 53:35
  Speaker 4: where we evolve our phages to try to have broader
• 53:38
  Speaker 4: host strange to be able to infect more different subtypes
• 53:41
  Speaker 4: of the same bacteria. You could also use molecules to
• 53:46
  Speaker 4: try to assist the infection, and that might make one
• 53:49
  Speaker 4: phage work in more context. Those are like two main
• 53:52
  Speaker 4: research areas in my lab. Actually, so that's possible, that's
• 53:55
  Speaker 4: still a science question. But then even just using exactly
• 53:59
  Speaker 4: the model of the l Yava Institute, I really love
• 54:02
  Speaker 4: that idea. I just don't know how it would work
• 54:04
  Speaker 4: in our current healthcare system. Maybe it has to be
• 54:07
  Speaker 4: more like the way that supplements are sold, where they're
• 54:10
  Speaker 4: generally regarded as safe, and so people could use phages
• 54:15
  Speaker 4: as a kind of augment, like an addition to their antibiotics.
• 54:19
  Speaker 1: Uh oh, are we walking towards the podcast supplement industry
• 54:23
  Speaker 1: that so many people get sucked into. We are not
• 54:28
  Speaker 1: building supplements here.
• 54:29
  Speaker 4: I was thinking more like a I think like a
• 54:32
  Speaker 4: wellness spot, Like apparently the onlyav Institute is an integrative
• 54:35
  Speaker 4: health center where you get a massage every day and
• 54:37
  Speaker 4: you meet with a team of doctors and psychiatrists and
• 54:40
  Speaker 4: everybody helps you get better. And so heck, yeah exactly.
• 54:43
  Speaker 4: So like, hey, we're in sunny Sokal, maybe we should
• 54:47
  Speaker 4: make a clinic some of us. Yeah, that's right.
• 54:51
  Speaker 2: Can we talk a little bit more about the trade off?
• 54:53
  Speaker 3: So you were talking about how your lab is trying
• 54:55
  Speaker 3: to evolve the phages to be able to attack more
• 54:57
  Speaker 3: kinds of bacteria.
• 54:59
  Speaker 2: So two thoughts.
• 55:00
  Speaker 3: One thought is that we talked earlier about how each
• 55:02
  Speaker 3: phage is usually specialized on one species or even strain
• 55:06
  Speaker 3: of bacteria. So I imagine it's very hard to evolve
• 55:08
  Speaker 3: it to be more of a generalist. And then two,
• 55:11
  Speaker 3: you know, one of the benefits of this technique to
• 55:13
  Speaker 3: me seems to be that you don't wipe out the
• 55:16
  Speaker 3: rest of your bacteria. You can like maintain your microbiome
• 55:19
  Speaker 3: and just target the bad guy. Yeah, so, like, what
• 55:22
  Speaker 3: are the trade offs with with trying to make a
• 55:25
  Speaker 3: more general phage.
• 55:26
  Speaker 4: Well, a more general phage would likely still be way
• 55:30
  Speaker 4: more precise than an antibiotic. So if you were to
• 55:33
  Speaker 4: take a phage that can kill most of your Enercoccus
• 55:38
  Speaker 4: fecalus or pick one of those escape pathogens, that would
• 55:41
  Speaker 4: still leave tons of other bacteria alone in a way
• 55:44
  Speaker 4: that antibiotics really never do. So I think it would
• 55:48
  Speaker 4: still be way more specific even with a more generalist phagel.
• 55:52
  Speaker 4: So then the question is just whether we can evolve
• 55:55
  Speaker 4: those generalist phages. For some industrial applications. There has all
• 56:00
  Speaker 4: already been signs of success for that, like, in fact,
• 56:02
  Speaker 4: the deli meat industry and the food spoilage industry have
• 56:08
  Speaker 4: been using phages for a long time and I think
• 56:11
  Speaker 4: that there's a lot of industrial know how that I
• 56:13
  Speaker 4: am not privy to that suggests that this has been possible.
• 56:16
  Speaker 4: So I don't know, but I think that there are
• 56:20
  Speaker 4: a handful of staphylococcus and lysteria and phages that are
• 56:24
  Speaker 4: used in the food industry that actually do have pretty
• 56:27
  Speaker 4: broad host range, So it could be that we could
• 56:30
  Speaker 4: use the same methods to make that happen for human
• 56:32
  Speaker 4: medicine too, But there's still it's just a totally different
• 56:36
  Speaker 4: regulatory framework than what we're used to for pharmaceuticals. So
• 56:40
  Speaker 4: it's an interesting thing. I'm so curious if in ten
• 56:44
  Speaker 4: years we're going to have this all figured out and
• 56:46
  Speaker 4: it's going to be widespread, or if it's still going
• 56:49
  Speaker 4: to be this kind of backwater. It's hard to know.
• 56:51
  Speaker 4: It feels like there's a sea change right now that
• 56:54
  Speaker 4: there are now hundreds of clinicians that are very interested.
• 56:57
  Speaker 4: But on average, if you go to your doctor and
• 56:59
  Speaker 4: ask a phage therapy, they're probably not going to have
• 57:02
  Speaker 4: heard of it, you know, or not know much.
• 57:04
  Speaker 1: And in that scenario, could phage therapy be a victim
• 57:06
  Speaker 1: of its own success? I mean, if you have these phages,
• 57:09
  Speaker 1: you start using them on bacteria, Are you then just
• 57:11
  Speaker 1: going to end up with bacteria that are resistant to
• 57:15
  Speaker 1: your phages? Couldn't it suffer the same fate as antibiotics.
• 57:18
  Speaker 4: Yes, bacteria will evolve resistance to the phages, and that's
• 57:23
  Speaker 4: exactly the same problem we have with antibiotics. You're right,
• 57:28
  Speaker 4: I guess I look at it like the bacteria and
• 57:31
  Speaker 4: phages have been in these arms races through the ages,
• 57:35
  Speaker 4: and what you're trying to do in an infection is
• 57:38
  Speaker 4: to give the immune system a leg up. And so
• 57:42
  Speaker 4: in an acute sense, what you need is like a
• 57:44
  Speaker 4: one two punch, and you could use antibiotics in phagies
• 57:47
  Speaker 4: at the same time, and you get in there and
• 57:50
  Speaker 4: you tap the infection down a bit, and you just
• 57:52
  Speaker 4: give the immune system a moment of breathing rooms so
• 57:55
  Speaker 4: that there's more chance for the human to survive the battle.
• 57:59
  Speaker 4: You know. So, yeah, it's true that there could still
• 58:02
  Speaker 4: be resistances arising to phages. But when people use that argument,
• 58:07
  Speaker 4: I'm always like, hey, well antibiotics. You know, bacteria resist
• 58:11
  Speaker 4: antibiotics too, and that didn't stop us from making good
• 58:14
  Speaker 4: use of them and figuring out treatment plans that set
• 58:18
  Speaker 4: things up so the human can succeed, So I think
• 58:20
  Speaker 4: we just need to learn how to do that, which
• 58:22
  Speaker 4: is very early days. As you can imagine, we've only
• 58:25
  Speaker 4: used phages, like, you know, a couple hundred times probably
• 58:28
  Speaker 4: in the United States in the last decades. So it's
• 58:31
  Speaker 4: not like if people ask you questions like, oh, should
• 58:34
  Speaker 4: we use this dose or that dose or this treatment
• 58:36
  Speaker 4: time or that treatment time. I mean, we do not
• 58:38
  Speaker 4: know the answer to things like that yet.
• 58:40
  Speaker 3: There's a final question we have to ask, which is
• 58:45
  Speaker 3: are there bacteria in space with phages? And are aliens
• 58:49
  Speaker 3: using phage therapy? How would you phrase the alien question
• 58:54
  Speaker 3: this time around, Daniel.
• 58:55
  Speaker 1: No, I've trained you well, Kelly, that was perfect. Yeah, yeah,
• 58:58
  Speaker 1: do aliens have viruses?
• 58:59
  Speaker 4: Could you know?
• 59:00
  Speaker 2: Well, am I in the whites and Institute? Now?
• 59:02
  Speaker 1: Yes, yes, we'll send you some salad dressing. Yes.
• 59:09
  Speaker 4: Well, we definitely have brought Earth's microbes out to space,
• 59:14
  Speaker 4: although there is a whole division of NASA aiming towards
• 59:17
  Speaker 4: preventing that from happening, so we work hard not to.
• 59:20
  Speaker 4: But microbes are everywhere, so of course we've brought some
• 59:23
  Speaker 4: out to space, so there's definitely going to be some
• 59:26
  Speaker 4: phages out there. Would be my guess. I mean, they're
• 59:28
  Speaker 4: probably not going to survive long. So would they make
• 59:30
  Speaker 4: it to where aliens are, I would say.
• 59:33
  Speaker 1: No, member would aliens have their own native viruses? Do
• 59:36
  Speaker 1: you think viruses are a common feature of life everywhere
• 59:39
  Speaker 1: in the universe?
• 59:40
  Speaker 4: Yes, I definitely do. I mean I think most life
• 59:42
  Speaker 4: will start from little self replicating things like are in
• 59:47
  Speaker 4: a world. I mean, that's the only model in my head.
• 59:50
  Speaker 4: So of course I need to meet an alien who
• 59:52
  Speaker 4: has a different model in their head to contradict it.
• 59:54
  Speaker 4: But I could imagine a totally different type of life
• 59:57
  Speaker 4: emerging with the same order of events, where you start
• 1:00:02
  Speaker 4: more from little self replicating things that essentially are viruses,
• 1:00:07
  Speaker 4: and in general, yeah, it's hard for me to imagine
• 1:00:10
  Speaker 4: an ecology that doesn't have infection and viruses going on.
• 1:00:14
  Speaker 1: So then, actually, my last question, Katrina is where do
• 1:00:17
  Speaker 1: your sympathies lie? I mean, you are growing up these phages,
• 1:00:21
  Speaker 1: you're attacking the bacteria, but you're also talking about the
• 1:00:23
  Speaker 1: bacteria getting stressed out. Are you in the camp of
• 1:00:25
  Speaker 1: the humans or the bacteria or the viruses? Really, where
• 1:00:29
  Speaker 1: should we put your allegiance?
• 1:00:30
  Speaker 4: I mean, I do not think you need to have
• 1:00:32
  Speaker 4: separate allegiances. This is like a big team dodging the question.
• 1:00:37
  Speaker 2: No he's not. That's a perfectly valid answer.
• 1:00:39
  Speaker 4: Okay, But here's what I'm saying. I think that the
• 1:00:43
  Speaker 4: bacteria are invited when they are behaving themselves. I mean,
• 1:00:48
  Speaker 4: I am not inviting crazy, infecting, drug resistant bacteria. Those
• 1:00:54
  Speaker 4: guys have gone too far, you know.
• 1:00:58
  Speaker 1: So there are some limits to Katrina's empathy. Even that's amazing.
• 1:01:01
  Speaker 4: But like an average bacteria is not a pathogen. But yeah,
• 1:01:04
  Speaker 4: the pathogens, they're like nihilists, you know, they're not invited.
• 1:01:07
  Speaker 2: Amen.
• 1:01:08
  Speaker 3: All right, Well, it has been a fascinating day here
• 1:01:11
  Speaker 3: at Daniel and Kelly's Viral Universe.
• 1:01:12
  Speaker 2: I always love having you on the show, Katrina.
• 1:01:15
  Speaker 4: Thank you well, thank you for having me, and thank
• 1:01:18
  Speaker 4: you guys for listening to phage therapy. And if your
• 1:01:20
  Speaker 4: listeners have any suggestions about how our community should get
• 1:01:25
  Speaker 4: phage therapy off the ground, we're really listening.
• 1:01:30
  Speaker 1: All right. So it's August twenty fifth, and we're checking
• 1:01:33
  Speaker 1: in for an update on that patient. Katrina, what is
• 1:01:36
  Speaker 1: the status of the patient that your lab developed a
• 1:01:38
  Speaker 1: page four?
• 1:01:39
  Speaker 5: Well, it's week four out of six now, so the
• 1:01:42
  Speaker 5: fifth week of treatment out of six will begin on Thursday,
• 1:01:46
  Speaker 5: so we don't have any knowledge yet of whether it worked.
• 1:01:49
  Speaker 5: We actually have to wait for a month after the
• 1:01:51
  Speaker 5: end of the therapy to see whether the fevers return
• 1:01:54
  Speaker 5: or not. And that's how we'll know whether the staff
• 1:01:56
  Speaker 5: causing sinusitis in the nose has been damp and hopefully
• 1:02:01
  Speaker 5: taken out by this page.
• 1:02:03
  Speaker 1: All right, well, because we're going to have to have
• 1:02:04
  Speaker 1: you back on the podcast for a follow up episode
• 1:02:06
  Speaker 1: to see how this stuff works.
• 1:02:08
  Speaker 4: I would love that great idea.
• 1:02:16
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• 1:02:20
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• 1:02:21
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• 1:02:24
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