Phage therapy (featuring Dr. Katrine Whiteson)

Daniel and Kelly chat with Katrine Whiteson about how we can enlist viruses to kill infectious bacteria.

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Episode Transcript

Speaker 1 (00:07):
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

(00:29):
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
one hundred years ago we discovered a powerful new ally.
Some fungi were the enemy of our enemy, able to

(00:51):
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

(01:14):
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. Welcome to Daniel and Kelly's extraordinarily individual universe.

Speaker 2 (01:49):
Hello, this is Kelly Windersmith.

Speaker 3 (01:50):
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. Hi.

Speaker 1 (02:02):
I'm Daniel. I'm a particle of physicists and professor at
UC Irvine, and I'm definitely the second most useful person
at the Whiteston Institute for Advanced Science.

Speaker 3 (02:10):
And the good news is today we're getting the first
most useful person back on the show.

Speaker 2 (02:15):
This is the third time.

Speaker 3 (02:15):
Katrina has joined you and I and I enjoy it
every single time.

Speaker 1 (02:19):
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.

Speaker 3 (02:28):
Yeah, and today we learn 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.

Speaker 1 (02:41):
You were hoping she was going to say parasites, wouldn't
you Well, I mean.

Speaker 3 (02:44):
The answer is a kind of parasite really or pathogen,
depending on how you find these things.

Speaker 2 (02:48):
So I felt very validated today during our conversation.

Speaker 3 (02:53):
But Daniel, if you had to guess what order of animals,
and remember it's Kingdom Philum class order or of animals
has the most species in it?

Speaker 1 (03:03):
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 you turn. I'm gonna have
to go beetles? Is it beetles or ants?

Speaker 3 (03:13):
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.

Speaker 2 (03:36):
Each of those beetles species.

Speaker 3 (03:38):
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, and
there's often more of those than there are the hosts.

(03:59):
Good luck, sleeping friends, And.

Speaker 1 (04:00):
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.

Speaker 3 (04:14):
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.

Speaker 2 (04:36):
Anyway, so there's always levels of infection going on.

Speaker 1 (04:39):
It's infection all the way down.

Speaker 2 (04:41):
It's amazing, sure is.

Speaker 1 (04:43):
And so on today's program we have my wonderful wife
and colleague at the Whites Institute who is coming back
to the podcast to tell us about how she personally
is developing treatments against resistant bacteria.

Speaker 2 (04:55):
Best whites in.

Speaker 4 (04:57):
Just kidding, just.

Speaker 1 (04:58):
Kidding, totally undrescent agree with you on that one. So
then it's my pleasure to welcome to the podcast Katrina Whitson.
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

(05:20):
the Whitsun 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.

Speaker 4 (05:36):
Thank you very much for the overly kind introduction.

Speaker 1 (05:42):
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.

Speaker 4 (05:50):
Okay, I could probably do that. I just hope this
time people would like to have a second helping that's all.

Speaker 3 (05:56):
Is this an inside joke? Does Daniel not have second helpings?
Of salad or something.

Speaker 1 (06:00):
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.

Speaker 4 (06:12):
Us only after they learned what I had put in there.
They were gobbling it up, just buying before I said anything.

Speaker 3 (06:21):
Oh, I see, I see you. We should never tell
people what's in the food until the end of the meal. Yeah,
but I imagine you could make a salad dressing with all
kinds of like microbiome related claims.

Speaker 2 (06:31):
I would probably buy it.

Speaker 4 (06:32):
It's true.

Speaker 1 (06:33):
But today we're not here to talk about how to
make your salad tastey. 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 and remind ourselves
what's going on with traditional antibiotics. So, like, give us
the very basics. When you take penicillin or you take amoxicillin,

(06:54):
what's going on? How do those work? How do those
help you combat pathogens?

Speaker 4 (07:00):
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 bacteria static,
so they'll halt the growth of the bacteria, they won't
directly kill them, and others are called bacteria cytle because
they can actually kill the bacteria. But the point is

(07:22):
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, and that's because the antibiotic is getting

(07:46):
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
what World War two and 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

(08:07):
to being able to survive infections that took people down
before the era of antibiotics and around the time of
World War two.

Speaker 2 (08:16):
I like that. I like that a lot for bacterio
static stuff.

Speaker 3 (08:21):
Is the goal here just that you are trying to
make sure they don't grow any more 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.

Speaker 4 (08:34):
I think either of those would be good outcomes. So yeah, okay,
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.

Speaker 2 (08:46):
Got it.

Speaker 1 (08:47):
And last time you're 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 towards pathogens or the things that
are hurting you, or is it just like an nuclear
bomb and it's just killing all of your microbes.

Speaker 4 (09:03):
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,

(09:26):
you're likely to kill bacteria that we're not causing any
trouble at all. So there's there's pros and cons to that.
On the pro side, you don't have to think too
hard about which antibiotic to take. That 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. And

(09:47):
to be honest, at the time when we started using
antibiotics in the mid twentieth 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

(10:08):
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.

Speaker 3 (10:17):
Totally okay 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

(10:37):
certain kinds of bacteria targeted?

Speaker 4 (10:40):
Some molecules are focused on certain subsets of bacteria. I mean,
for example, tobramycin is a recently developed antibiotic that people
as cystic fibrosis used to treat pseudomonous infections in their lungs,
and so that has relatively targeted action, but of course
it can still understanding is that it can still kill

(11:02):
other gram negative bacteria. There's a few big categories of bacteria,
and some antibiotics target broadly those categories. So if you
to 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. So a mira penem,

(11:23):
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

(11:43):
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
clusterradia defecal that causes recurrent diarrhea.

Speaker 1 (12:05):
All right, So for hundreds of thousands of years, if
you've got an infection you scratched your leg or whatever,
you are at risk of dying. And then for fifty
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,

(12:28):
Why are we hearing so much about antibiotic resistance? Why
are these things not working anymore?

Speaker 4 (12:33):
Great question. Well, to be honest, every time we've started
using an antibiotic, within five or ten 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 twentieth century, you know, we got penicillin, and
within a couple of years we had, you know, bugs

(12:55):
that could resist the antibiotic penicillin. But then we would
come up with new abiotics, and so during the second
half of the twentieth 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. There's

(13:15):
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

(13:37):
a new antibiotic, the doctors are going to conserve it
because they don't want new resistances to emerge. They're going
to be like, oh man, this is my lucky ticket.
I'm saving this for the moment I really really need it.
But that's going to 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

(13:57):
real slow down in the pipeline of the discovery of antibiotics.
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 ninety nine
percent of what's out there. So it's very impossible to

(14:19):
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 are pharmaceutical companies or even healthcare

(14:43):
companies 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 Blockbuster's statins or ozembic, you know, antibiotics are
just never going to be as lucrative. So that's a

(15:06):
real problem. And then I guess another thing I absolutely
have to say is that about eighty percent 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
antibiotics stewardship programs, the main way that we use antibiotics,
and probably where a lot of the resistances are arising,

(15:29):
is in agriculture. So that's where we could make a
lot of gains if we could reduce the use of
antibiotics and 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,

(15:52):
they would say. Yes. It was so hard to get
out of the social pressure of doing something you were
accustomed to.

Speaker 1 (15:59):
But is this because like cows are getting scratches in
the need treatment or is it just like they're pumping
antibiotics in because it makes them grow faster.

Speaker 4 (16:06):
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 put that energy into beefing yourself up or literally.

Speaker 1 (16:28):
Or poorking out a little bit.

Speaker 3 (16:29):
Yeah, 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 the same
reasons you mentioned, they've been holding back because they want to, like,

(16:51):
you know, make sure they can save it for the
special cases or whatever. But there's all these people who
need it now, 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 microevolutionary process
that results in antibiotic resistance.

Speaker 4 (17:12):
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 of cell copies,

(17:35):
there could be a mutation in there. So when we
talk about antibiotic resistance, 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 antibiotics.

(17:57):
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 read for resistance, and that's
already like that at the beginning, before you even took
the antibiotic. Then when you take the antibiotics, some of
those cells survive. So that I think is a conceptual
difference between how most of my students think it happens

(18:20):
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. Others have mutations in a part of

(18:43):
the cell that the antibiotic is trying to target. So
it's just like kaping, it doesn't do anything. In fact,
there's are 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 trade become enriched in a community, they can start
to spread them to other cells nearby. You've probably heard

(19:05):
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 a number of different mechanisms for how

(19:27):
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.

Speaker 2 (19:35):
That's really interesting.

Speaker 3 (19:36):
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

(19:57):
share the traits for resistance between them, which speeds up
the rate of resistance moving through the population. Is it
would that be fair to say, yeah, ah, bacteria are tricky.

Speaker 4 (20:08):
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 traits

(20:30):
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. So

(20:50):
there's a lot of situations in our modern world that
push bacteria towards having these traits that help them resist
antibiotics direct.

Speaker 1 (20:58):
I think there's a major misconception and 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 exactly.

Speaker 4 (21:19):
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.

Speaker 1 (21:38):
And what kind of infections typically cause trouble? Are there
some kinds that are more likely to have bacteria.

Speaker 4 (21:45):
That are resistant, 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 enter caucus Staphylococcus,
club Ciela, Acinitobacter, Pseudomonas enterobacter. And sometimes we say escape

(22:05):
to add eqalie.

Speaker 3 (22:06):
I mean, I would have guessed. I would have guessed
that's what that Acroym meant.

Speaker 1 (22:10):
I totally have all those in the top of my head. Also,
let's just hope you don't put those into a salad dressing.
It sounded like a recipe.

Speaker 4 (22:17):
Oh my gosh.

Speaker 1 (22:18):
Yeah.

Speaker 4 (22:18):
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 Stina tripomonas, also berkel darrhea. Those are
gram negatives. We sometimes call them water levers. You find
them in tap water, Like, they can live in tap water,

(22:39):
isn't that amazing? And they can live in soil, so
they're You're often exposed to them in water or outside,
and if your immune system is compromised, they can cause
a lot of trouble.

Speaker 1 (22:50):
Sorry, why is it amazing they can live in tap water?
I can live in tap water?

Speaker 4 (22:55):
How long? Though? I mean you could. It's true. Water
will sustain a human for like a little while, but
at some point you're gonna need some calories and.

Speaker 2 (23:01):
You're gonna get pruney.

Speaker 1 (23:02):
Oh mean they can eat tap water like that's their
only source of calories. That's amazing.

Speaker 4 (23:07):
I see, okay, exactly, Wow, that is amazing. Like, if
you pick up a bottle of water at the store,
it probably has some of those cells in there. And
I don't mean to make people not want to drink water,
because when I hear that there's microbs in something that
doesn't creep me out, I'm just like, oh cool, I'm
happily you know, living among them. So I'm not saying

(23:27):
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.

Speaker 3 (23:37):
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?

Speaker 4 (23:45):
Those are well, the list I just gave you are
of common infections that are frequently becoming resistant to antibiotics
in a way that's untreatable. So for each of them,
there's 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 you

(24:09):
just have to switch antibiotics a few times, but eventually
you find one that works, and sometimes meaning that you
like literally never find an antibiotic that works. And so
there are a lot of people in the world right
now who have chronic infections that they cannot clear, like
from urinary tract infections are a really really big one.
Sometimes lung infections. Wound infections can last forever and just

(24:32):
be very very hard to treat. And they're hard to
get the medicine too 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

(24:53):
under good circumstances. But if your immune barriers break down,
which can even just mean a scrap on your skin,
like you could be a healthy person who just gets
a scratch, and then all of a sudden, staff that
was happily living in normal amounts on your skin can
then cause a terrible infection.

Speaker 3 (25:11):
Well, I've discovered a new thing to fixate on tonight.
That's what's gonna 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.

Speaker 1 (25:46):
Okay, we're back, and Kelly is covering herself with bubble
wrap to protect herself from the future of infections.

Speaker 2 (25:55):
I can't imagine a chronic uti. That sounds awful.

Speaker 4 (25:58):
It does sound awful, doesn't it.

Speaker 1 (26:00):
Kachina has a salad dressing that'll fix that for you.

Speaker 3 (26:02):
Oh my gosh, Oh that's great, that's great, or cranberry
pills or something. But anyway, all right, so we talked
about how antibiotics are not working anymore in a lot
of cases, and so you work on phage therapies.

Speaker 2 (26:14):
So what is a phage.

Speaker 4 (26:17):
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 ten 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,

(26:38):
for all of the bacteria that we've talked about, there's
usually about ten 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.

Speaker 2 (26:57):
Do the viruses have viruses?

Speaker 4 (26:59):
Yeah, while there's actually yet maybe they do. Actually there's
kind of little hitchhiker DNA pieces that could be considered
viruses on viruses. So yeah, it never ends.

Speaker 1 (27:10):
Okay, And should we think of these viruses the way
we think of our microbial community, like are they sometimes
helping the bacteria sometimes it's not so clear, sometimes hurting them?
Or are they're always invading and taking over? Is there
always a negative relationship between the viruses and the bacteria.

Speaker 4 (27:25):
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

(27:47):
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.

Speaker 1 (27:56):
You know, viruses are here to stay, you're saying.

Speaker 4 (27:58):
They're here to say, and they are 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

(28:19):
out by transmitting information.

Speaker 1 (28:21):
I don't know how to feel about this. At first,
I was like, bacteria are pathogen, They're hurting us, they're
killing people, they're painful. UTI is 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, Patrina?

Speaker 4 (28:35):
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 fewer pathogens. It's just
the ones on the news are pathogens. They should write

(28:55):
more positive stories about helpful microbes should.

Speaker 3 (28:59):
I do see a lot of them, although they're not
very good scientifically, but always But okay, So if every
bacteria has ten viruses, does that mean that viruses are
the most like diverse and specios life on the planet
or is are the same viruses infecting lots of different
kinds of bacteria?

Speaker 4 (29:18):
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 ten to the thirty one. If you
line them up head to head, they go to the
edge of the galaxy back and forth a bunch of times.

(29:39):
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 pseudomonis also able
to infect a different bug that staphylococcus or something like that.
Typically know, in fact, it's at a substrain level. A

(30:00):
phage that infects one pseudomonis. It's it's like a sub
type of pseudomonis, Like like any type of bacteria has
genus and species names. You know, King's play chests on
fine grain sand. The taxonomy going down to genus and species.

Speaker 2 (30:15):
Oh, you learned a nice one.

Speaker 4 (30:18):
Yeah, there's probably less of for a free ones going
around the schoolyard.

Speaker 2 (30:21):
Yea, I won't repeat mine.

Speaker 4 (30:23):
Go ahead, And so there's even substrains, So like Pseudomonius
originosa is a genus and species name, but there's subtypes
beyond that, and whether the phage infects is usually at
a sub type level like that, and it's kind of
interesting to think about it. I mean, the bacteria are
constantly making small mutations to resist the phages, so the

(30:47):
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
and it's like very conserved, and if you looked back
in the history of bacteria, you'd see big movement towards like, oh,

(31:07):
now they can use oxygen or something like that. Phage
infection is like a tiny little thing. It's very easy
to change it. It's at the tippy tippy branches of
the toxinomic trees.

Speaker 1 (31:16):
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

(31:38):
if they can use bacteria.

Speaker 4 (31:39):
Well, I think there is an ocean of viruses out
there that never get to infect a cell. So they
have kind of an unrequited dream of finding a host
and they just never do. However, the dark virus, the
lonely ones.

Speaker 1 (31:55):
But now you're making a sympathetic to viruses, Katrina, You
are too empathetic.

Speaker 4 (32:00):
But so, yes, there's going to be viruses out there
that never get to infect a sell. 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

(32:21):
than training one kid with lots of skills and hoping
they'll find a job in a changing world, it's like,
you got to raise billions of viruses and a few
of them will continue to be able to infect. And
I mean it's been going on for a long time,
and in a way it's quite stable. Like if I
took samples from anybody listening to this podcast right now,

(32:42):
and then in five more years took another sample, most
of the gut viruses 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

(33:02):
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.

Speaker 1 (33:19):
So we are the interlopers, the weird ones in a viral.

Speaker 4 (33:22):
World, Right, That's certainly one way of looking at it.
I mean, I think we have some advantages. I think
consciousness does have a does distinguish us from viruses.

Speaker 2 (33:34):
There's days when I'd rather not have consciousness.

Speaker 3 (33:37):
But anyway, Okay, so we've got viruses and some of
them are bad for bacteria. How do we harness that
to fight bacteria?

Speaker 4 (33:46):
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 nineteen fifteen or nineteen seventeen, 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

(34:08):
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.

Speaker 1 (34:19):
Wastewater is such a euphemism. I mean, you're talking about
poop to pills, right, We're like finding medicine in sewage.

Speaker 4 (34:26):
Sewage is such a concentrated way to grab the microbes
of humanity that it's a very tempting place to look. Yes,
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

(34:46):
sixteen million people. Wow, from just eight samples.

Speaker 2 (34:50):
You are the queen of silver linings.

Speaker 1 (34:53):
Sewage is so tempting, said nobody.

Speaker 5 (34:55):
Ever.

Speaker 1 (34:56):
Anyway, maybe we're not going to put you charge of
marketing and flavors for the new cell addressing company. 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 exactly.

Speaker 4 (35:16):
So you take the infecting cells, you mix them with
some wastewater, and then we use a technique. I mean,
I need slides. Man, This is hard on a podcast, but.

Speaker 2 (35:29):
I don't want to show you guys pictures it is.

Speaker 4 (35:31):
But you know, you make a plate of the bacteria
mixed with the material that you hope has phages in it.
And an important thing to say is that we filter it.
We try to get the cells out of there. So
it's just viruses left behind, because otherwise you might imagine
everything from the whole wastewater treatment plant growing on your plate.
But actually you filter and hopefully there's viruses in there

(35:52):
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.

Speaker 1 (36:06):
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 and one of them goes in.

Speaker 4 (36:12):
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 Ourstina tri Promona's project,
the wastewater in Escondido is like amazingly good. So if
I get astino infection, I'm like telling the students, please
get the Escondido wastewater.

Speaker 1 (36:30):
What are they eating in Escondido or.

Speaker 4 (36:32):
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 Stina Tripromona's phages.
But when we use Escondido wastewater. We've even sent our
Escondido wastewater to collaborating labs and they've also succeeded.

Speaker 1 (36:49):
It's liquid gold.

Speaker 4 (36:50):
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.

Speaker 1 (37:10):
Right back up and explain what you were talking about.
There a white bacterial.

Speaker 4 (37:14):
Lawn, so you'll have a plate of bacteria that look white.
So you'll have like a flat white background.

Speaker 1 (37:21):
Why do they look white.

Speaker 4 (37:22):
Well, some bacteria are a little bit yellow, or most
bacteria are white or yellow. Sometimes they turn a little blue.
But the point is you have a clear growth of
cells on your plate. And then you can see with
your naked eye that there are clearance zones from the
viruses and so that represents if one virus infects one

(37:42):
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

(38:03):
of the plate. And you can see that.

Speaker 1 (38:05):
And how do you know which virus has done it?

Speaker 4 (38:07):
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

(38:29):
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 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 two hundred phages, and then we'll

(38:49):
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.

Speaker 1 (39:09):
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. Yeah, another
lab has a different set. This is like Katrina's personal
phage arsenal.

Speaker 4 (39:20):
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

(39:40):
money off of them, so then nobody would ever invest
in what we need is for like real investment to
get this thing off the ground, you know, all right.

Speaker 1 (39:48):
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?

Speaker 4 (40:03):
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,

(40:25):
and it's like a twenty four 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

(40:46):
deal with.

Speaker 1 (40:46):
Phages difficult to deal with. Like they send grumpy emails
late at night or what's going on.

Speaker 4 (40:51):
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 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.

Speaker 3 (41:06):
It's biology, So it depends, yes, And by a 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.

Speaker 4 (41:14):
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?

Speaker 3 (41:26):
So each time you're picking the viruses that killed the
bacteria and putting them onto a new plate exactly and
hoping to get a pure culture eventually.

Speaker 4 (41:33):
Exactly, and then 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

(41:54):
call them stationary phase. You know, they're like not as
actively growing anymore. And viruses have all different mechanism as
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

(42:14):
different types of media growth, and we'll try like triangulating
all the conditions to learn what this particular virus likes
the best, so then we can do a better job
of propagating it in successful conditions.

Speaker 3 (42:26):
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.

Speaker 1 (42:52):
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 whose doctor emails her and asks her if she's
got something cooking up in the freezer that can kill
their bacteria. So we've heard about how you find a
fade that can help infect your bacteria, you purify, you isolated.
How do you actually go all the way to putting

(43:14):
it back into human and treating them.

Speaker 4 (43:17):
Well, that's a really big question, but it's actually an
old question. So since around nineteen twenty, 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 Two as well, Like for example, when Elizabeth

(43:38):
Taylor was filming Cleopatra, I think she was in the UK,
she got a terrible staff 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 Tiblis, Georgia, which is probably the
most famous of these centers, they've been using phage therapy
to treat infections for more than a century and so

(44:01):
they it's the 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

(44:23):
medication that your doctor can prescribe. So all of it
is happening through labs like mine and through applications to
the Federal Drug Administration asking for an exemption, either as
an emergency authorization or as a compassionate use exemption. So
it has to be a situation where somebody's in really

(44:44):
dire straits and taking on the risk of an experimental
treatment makes sense. So in my lab, for many years,
I've been growing up these phages out of wastewater, and
people were sometimes sending me their patient's isolates and asking
if we had a phage, and we almost always succeeded.
That was not the bare, but usually the person would
either get better or pass away before we could get

(45:06):
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 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

(45:28):
to the Infectious Disease Department Grand Rounds at UC Irvine
where I work, and I talked to all the doctors
about it, and I got a lot of help from
Jessica Satcher of the Phage Directory. This was her idea,
I think, actually, and we talked about how we should
aim for people who are not quite so acutely ill,
people who have a more chronic infection, where their life

(45:49):
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
twenty twenty five. So since then I've had ten 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 page to a person step. And

(46:11):
it's all thanks to a student named Ritwick Kumar. You know,
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,

(46:34):
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 Lude Miller, and Alexandra I
named her Lude Miller and so since last summer we

(46:54):
have been prepping this phage Ludmilla to help a patient
at the CI Medical Center who as a chronic sinusitis
with MRSA meth cylline 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

(47:17):
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 darray Vantyne's
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,

(47:40):
because it doesn't carry endotoxins, which are really hard to
purify out of bacterial preps. So it kind of made
the process simpler by starting with a gram positive anyway,
so Ritwick made a big batch of these phages.

Speaker 1 (47:53):
He stewed up some lud Milli soup, he.

Speaker 4 (47:56):
Stewed up some lud Milli soup, and then he filtered
out all the stuff that could cause trouble. And I mean,
I probably should not go into so many details about
the protocol, but ask questions if you're interested. 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 storility and endotoxin. And because

(48:17):
I didn't want it to be just like yeah, I mean,
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 fifty 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,

(48:40):
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 Eliava Institute's century of experience. Now
in the United States, there's been several hundred cases in

(49:00):
the last couple of years, and I'm not aware of
any adverse events.

Speaker 3 (49:04):
And by that you mean nobody's had like a weird
immune response to getting viruses put in them, Like, yeah,
everybody's fine. Maybe it doesn't kill the bacteria, but it
doesn't hurt.

Speaker 4 (49:12):
The people exactly. The person doesn't have a negative reaction
to the treatment so far. I mean, it's still experimental,
but so far there haven't been people having negative reactions. Great.

Speaker 1 (49:25):
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 happens.

Speaker 4 (49:36):
Yeah, did Ludmilla helpful? 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 forrinstance 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

(49:58):
the moment of truth will about three to four weeks
after the six weeks treatment because usually after the antibiotics
are stopped, the fevers come back. So we're gonna wait
to see if the fevers do not come back at
the end of the six weeks.

Speaker 1 (50:14):
All right, Well, we're recording this episode in mid August,
but we're gonna post it later, so just before 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.

Speaker 4 (50:27):
Oh what a good idea. I'm excited, but there's I mean,
there are actually a lot of interesting cases to follow.
In fact, I was at the Evergreen Phage meeting in Knoxville, Tennessee,
last week, and I met a man who has been
coming to the meeting a couple of times who had
a really terribly coli infection, and he actually traveled to
the Eliava Institute and too Blisi, Georgia, where they do
these phage treatments. They cooked up a specific phage just

(50:50):
for his infection because none of the ones in their
bank were effective, and the doctors there had him do
three twenty day courses of three times a day phage
treatment and it wasn't until the second twenty day course
that he started to feel better and then his bacterial
load and his blood dropped. So it's not necessarily that

(51:14):
you would see a big effect in the first couple weeks,
like in his case, at least it took several times,
and he wrote a book about it. He's been on
a lot of podcasts. It's a really really cool story.
So I'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 seventy five to eighty percent of people have

(51:34):
a positive responses and like their infection is helped.

Speaker 2 (51:37):
Wow, but it's still.

Speaker 4 (51:39):
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. Then, know how is

(52:00):
you know something that a good student can learn how
to do.

Speaker 3 (52:02):
I mean, we've known about this for one hundred 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?

Speaker 4 (52:11):
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 of one of them
in a trial that these days would cost one hundred

(52:32):
million dollars 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

(52:53):
for phages because you need different ones for each infection.
So that's the real reason that it's not happening as
much right now. I would say, how do you.

Speaker 1 (53:02):
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
wide threaten?

Speaker 4 (53:15):
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

(53:38):
host strange to be able to infect more different subtypes
of the same bacteria. You could also use molecules to
try to assist the infection, and that might make one
phage work in more context. Those are like two main
research areas in my lab. Actually, so that's possible, that's
still a science question. But then even just using exactly

(53:59):
the model of the l Yava 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.

Speaker 1 (54:19):
Uh oh, are we walking towards the podcast supplement industry
that so many people get sucked into. We are not
building supplements here.

Speaker 4 (54:29):
I was thinking more like a I think like a
wellness spot, Like apparently the onlyav Institute is an integrative
health center where you get a massage every day and
you meet with a team of doctors and psychiatrists and
everybody helps you get better. And so heck, yeah exactly.
So like, hey, we're in sunny Sokal, maybe we should
make a clinic some of us. Yeah, that's right.

Speaker 2 (54:51):
Can we talk a little bit more about the trade off?

Speaker 3 (54:53):
So you were talking about how your lab is trying
to evolve the phages to be able to attack more
kinds of bacteria.

Speaker 2 (54:59):
So two thoughts.

Speaker 3 (55:00):
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. Yeah, so, like, what

(55:22):
are the trade offs with with trying to make a
more general phage.

Speaker 4 (55:26):
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 Enercoccus
fecalus 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

(55:48):
still be way more specific even with a more generalist phagel.
So then the question is just whether we can evolve
those generalist phages. For some industrial applications. There has all
already been signs of success for that, like, in fact,
the deli meat industry and the food spoilage industry have

(56:08):
been using phages for a long time and I think
that there's a lot of industrial know how that I
am not privy to that suggests that this has been possible.
So I don't know, but I think that there are
a handful of staphylococcus and lysteria and phages that are
used in the food industry that actually do have pretty
broad host range, So it could be that we could

(56:30):
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 an interesting thing. I'm so curious if in ten
years we're going to have this all figured out and
it's going to be widespread, or if it's still going
to be this kind of backwater. It's hard to know.

(56:51):
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 a phage therapy, they're probably not going to have
heard of it, you know, or not know much.

Speaker 1 (57:04):
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.

Speaker 4 (57:18):
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

(57:38):
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 in phagies
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 rooms so
that there's more chance for the human to survive the battle.

(57:59):
You know. 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

(58:20):
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 decades. 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.

Speaker 3 (58:40):
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.

Speaker 1 (58:55):
No, I've trained you well, Kelly, that was perfect. Yeah, yeah,
do aliens have viruses?

Speaker 4 (58:59):
Could you know?

Speaker 2 (59:00):
Well, am I in the whites and Institute? Now?

Speaker 1 (59:02):
Yes, yes, we'll send you some salad dressing. Yes.

Speaker 4 (59:09):
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

(59:30):
it to where aliens are, I would say.

Speaker 1 (59:33):
No, member would aliens have their own native viruses? Do
you think viruses are a common feature of life everywhere
in the universe?

Speaker 4 (59:40):
Yes, I definitely do. I mean I think most life
will start from little self replicating things like are in
a 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

(01:00:02):
more from little self replicating things that essentially are viruses,
and in general, yeah, it's hard for me to imagine
an ecology that doesn't have infection and viruses going on.

Speaker 1 (01:00:14):
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?

Speaker 4 (01:00:30):
I mean, I do not think you need to have
separate allegiances. This is like a big team dodging the question.

Speaker 2 (01:00:37):
No he's not. That's a perfectly valid answer.

Speaker 4 (01:00:39):
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.

Speaker 1 (01:00:58):
So there are some limits to Katrina's empathy. Even that's amazing.

Speaker 4 (01:01:01):
But like an average bacteria is not a pathogen. But yeah,
the pathogens, they're like nihilists, you know, they're not invited.

Speaker 2 (01:01:07):
Amen.

Speaker 3 (01:01:08):
All right, Well, it has been a fascinating day here
at Daniel and Kelly's Viral Universe.

Speaker 2 (01:01:12):
I always love having you on the show, Katrina.

Speaker 4 (01:01:15):
Thank you well, thank you for having me, and thank
you guys for listening to phage therapy. And if your
listeners have any suggestions about how our community should get
phage therapy off the ground, we're really listening.

Speaker 1 (01:01:30):
All right. So it's August twenty fifth, and we're checking
in for an update on that patient. Katrina, what is
the status of the patient that your lab developed a
page four?

Speaker 5 (01:01:39):
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 staff
causing sinusitis in the nose has been damp and hopefully

(01:02:01):
taken out by this page.

Speaker 1 (01:02:03):
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.

Speaker 4 (01:02:08):
I would love that great idea.

Speaker 3 (01:02:16):
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