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side. That's

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science.org/news. Click

1:50

subscribe. This

1:53

is the science podcast for April

1:55

19th, 2020. I'm

2:00

Sarah Kressy. First

2:02

up on the show, staff writer Paul

2:04

Voussin is here to talk about how

2:06

reductions in air pollution may lead to

2:08

a warmer planet. Next

2:11

I'm joined by contributing correspondent Andrew Curry. We're

2:13

going to discuss what appear to be ritual

2:16

killings carried out in neolithic

2:18

Europe. We talk about

2:20

how these gruesome deaths actually resemble

2:22

some modern-day mafia killings. Finally,

2:25

we have researcher Eric Nelson to talk

2:27

about how cholera is fighting a war

2:29

on two fronts. Actually, this is

2:31

the cholera bacteria, which can

2:34

be killed by antibiotics, but it's

2:36

also hunted inside the gun by

2:38

a bacteria-killing virus. It

2:40

turns out the dynamics between the

2:43

virus, the bacteria, and antibiotics are

2:45

important to understanding the course of

2:47

the disease. This

2:52

past year, 2023, was the hottest

2:55

on record, and these

2:57

high temps support the idea that

2:59

global warming, climate change, is accelerating

3:01

at an unexpected rate. This Week

3:03

in Science, staff writer Paul Voussin wrote

3:05

about a possible contributing factor, cleaner

3:08

skies leading to more absorption of solar

3:10

energy at the surface. Hi

3:12

Paul. Hi. Welcome back to the podcast.

3:14

Thank you. I found this a little

3:16

confusing. The first time I heard about it, isn't

3:19

absorbing radiation from the sun kind of the

3:21

main driver for global warming? How

3:23

is what we're talking about today something different?

3:26

There's this thing called the albedo of

3:28

the Earth, and that's the amount of

3:30

light that we reflect back into space.

3:33

Over the past couple of decades, there's these

3:36

instruments in space that have been monitoring. They

3:38

look at both the energy being reflected and

3:40

then the kind of heat being

3:42

given off by the planet. We can tally those

3:44

together compared to the energy we know that's coming

3:47

from the sun, and you get

3:49

the amount of excess energy in the planet.

3:52

Over this time, especially in the last

3:54

decade, the planet has became less reflective,

3:56

so more sun is not being

3:59

reflected off before. before it hits the

4:01

surface of the Earth. So at the

4:03

ground level, essentially, it's getting sunnier. This

4:06

is something I've heard about before when we talk

4:08

about shrinking of the ice caps, that means we'll have

4:10

less reflectance. But this is a more general

4:12

process, like over the whole surface of the

4:14

planet. There are a lot of different things

4:16

that can contribute. It's not just cleaner skies,

4:18

it's clearer skies, really. One big

4:21

part of this is atmospheric pollution, a

4:23

decline in atmospheric pollution that would otherwise

4:25

be reflecting light, but that's not necessarily

4:27

the whole story of this. There's a

4:29

lot of this that right now is

4:31

just a big mystery. Climate scientists don't

4:33

understand why it's getting less reflective. It

4:35

could be other changes with the clouds

4:37

that are not tied to

4:39

pollution, or it could be shifting

4:41

circulation, like air, ocean circulation, things

4:44

like this that are just not

4:46

quite understood yet. Pollutants would have

4:48

contributed to darker skies or less

4:50

clear skies because there's particulates and

4:52

aerosols, and that shines light

4:54

back into the sun. One of

4:57

the primary things here is sulfate

4:59

aerosols, so you have sulfur dioxide

5:01

that comes out of power plants,

5:03

dirty power plants, and creates these

5:05

little reflecting aerosols that shoot light

5:07

back. They also interact with clouds

5:09

and cause clouds to get brighter, give them

5:12

little cloud nuclei to make them more reflective

5:14

or last longer in the atmosphere. Just how

5:16

powerful both of these are is another big

5:19

uncertainty in climate. And what about the timing?

5:21

You said this is something that's been

5:23

observed a lot more in the last decade,

5:25

but we've been cleaning up

5:27

the atmosphere for some time in various

5:30

parts of the planet, not regularly around

5:32

the whole sphere. In some ways, this

5:34

is expected, at least part of it,

5:37

not unexpected. We've known that curbing pollution,

5:39

which is a good thing, causes

5:43

lots of deaths. You don't want to

5:45

keep pollution just to limit warming. That's

5:47

far worse a problem than warming. This

5:50

is built into climate models to the

5:52

extent that declining pollution will see warming

5:55

ramp up. And Even in the predictions

5:57

of climate models, warming does ramp up,

5:59

accelerating. Some because these aerosols were

6:01

doing that. Now he has happened. The

6:04

seventies is going on. Word is also

6:06

worth it. Suggests that. When. You

6:08

clean up their pollution to the same

6:10

kind of really dirty places. It can

6:12

take a couple of decades actually really

6:14

make a difference which is someone counter

6:17

intuitive you think of they stop the

6:19

person They things to change right away

6:21

but some clouds are most sensitive to

6:23

the first bits of hallucinate. Get your

6:25

as your rant been done the pollution

6:27

The class might not necessarily be changing

6:30

that much until you really get low

6:32

know some of this will receive Now

6:34

could be tighter reductions from the late

6:36

nineties really. Say. Time lot of

6:38

an unknown combat. One thing that I was

6:40

wondering about as you know are taken out

6:42

this excess energy absorption by the santa In

6:44

part is that compared. To what Anthropogenic

6:47

gases are doing. like the global

6:49

warming part as what's happening. I'm

6:51

really tried to tease apart this

6:53

difference between what we're tag my

6:56

hair like clear skies, this increase

6:58

absorb sad and anthropogenic climate science

7:00

from greenhouse gases. Like how do

7:02

these things compare to each other?

7:05

It can be potentially large from

7:07

the short term. Or he

7:09

keeps game bayer year after year. That's

7:12

the kind of inox or a ball

7:14

C O two rise in the atmosphere.

7:16

it becomes more and more powerful by

7:18

the over say this past twenty years

7:21

this model in study looked at been

7:23

increased energy in the system over that

7:25

time So from two thousand to twenty

7:27

nineteen Pm x amount of energy new

7:30

energy in the system may be forty

7:32

percent of that. he came from a

7:34

decline in reflexivity and potentially driven by

7:37

these reduction pollution be other part. Would.

7:39

Be crazy. Greenhouse gases mostly.

7:41

Oh wow. Okay to expect

7:43

this. Increase in energy absorption to

7:46

had of level out or the reverse.

7:48

while their greenhouse gases act as it's

7:50

ramping up, this is one of the

7:52

big question. This is like a big

7:54

difficult the grass question and climate science

7:56

because if this is just driven by

7:59

declining pollution right. Then okay, we get

8:01

there and then it is not gonna

8:03

keep happening right? You can only get

8:06

so clean. Lovely. Def fear clean skies.

8:08

Write a short term thing. It's really

8:10

unveiling some of the warming that we

8:13

have blocked before, but if there's

8:15

something else going on which animals

8:17

can't really explain everything it seems

8:19

right now. like if some clouds or

8:21

change in some ways that could continue

8:23

and is just totally not understood. there

8:26

are reasons to think that there is

8:28

something else going on because. What

8:30

these instruments and space called series

8:32

they see the reflectivity of the

8:34

planet decline in both hemispheres like

8:36

northern Southern hemisphere was pollution is

8:38

really dropped to the northern hemisphere

8:40

so like what's going on down

8:43

into southern hemisphere I said big

8:45

question. The. Kind of models only

8:47

go up through Twenty nine P and sell

8:49

Something different might have been happening in the

8:51

past few years and and we won't be

8:53

able to tell. Yeah, I models projections obviously

8:55

go out for. Hundreds. Of years

8:57

the as you say but when you are

9:00

trying to use real world data to constrain

9:02

with their depth to enter understand kind of

9:04

near term. Now you do things like you

9:07

put in the actual sea surface temperatures that

9:09

were experienced some of that time seeking kind

9:11

of recreate the weather a bit more closely

9:13

or this real world data for how much

9:16

pollution there wasn't that can. Help.

9:18

You actually figure out what's going on

9:20

vs it. just go in freely and

9:22

cream some earth that kind of like

9:24

the earth but not quite like the

9:26

earth as the state bureaucracy to climate

9:28

modeling that revolves around the Un climate

9:30

reports. Said. They put plans together,

9:33

the last generation was finalized and twenty

9:35

seventeen the plans for it in the

9:37

sticks. Time to get the new data

9:39

and update. All this but one thing

9:42

is people are pushing that we the

9:44

do this more frequently to understand near

9:46

term mysteries that might arise speaking as

9:49

continuing. Modeling continued measuring.

9:51

These series satellites is instruments

9:53

up other satellites. They're not

9:55

gonna be around forever are. We going to

9:57

be able to keep observing. This scene is in.

10:00

energy on the surface? It's quite possible.

10:02

There could be a big gap. So

10:04

right now there are six total instruments.

10:06

Four of them are on these workhorse

10:08

amazing satellites that have been up for

10:10

20 years or more than 20 years,

10:12

but their orbits are now drifting and

10:14

they're gonna go kaput in a couple

10:17

more years. Even now it's not

10:19

getting the same type of data because their

10:21

orbits are drifting. So they're essentially not that

10:23

useful for the climate record. Fifth

10:25

satellite, it's a weather satellite that's going to

10:27

go out of service likely the next few

10:29

years. And so the last instrument is on

10:31

kind of a flagship weather satellite

10:34

for the US. And it should keep going

10:36

until the successor comes up in

10:39

maybe 2028, but to single point of failure.

10:41

So some bit goes wrong or

10:43

gets struck by radiation and then that record

10:46

goes silent. And these are such a

10:48

small, so like the amount of energy coming in

10:50

and leaving the planet is like huge. And global

10:53

warming is 1% signal within

10:55

that. So you need

10:57

to have this trend continuing to be

11:00

able to like ease out anything. So

11:02

a gap here is more damaging than

11:04

some other satellite records I'd say. Thanks

11:07

so much for talking with me Paul. Oh yeah, no problem.

11:09

Paul Vousin is a staff writer for science.

11:11

You can find links to the stories

11:13

we discussed at science.org/podcast. Stay

11:16

tuned for a chat with me and

11:19

Andrew Curry about human sacrifice in Neolithic

11:21

Europe. Researchers

11:29

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on the right side. Okay,

13:25

just a quick warning for listeners that might be

13:27

sensitive to descriptions of violence.

13:44

This is going to be a little bit graphic. We're

13:46

going to talk about a way of murdering people. The

13:49

story is about what looks like

13:51

ritualistic killings of people in neolithic

13:53

Europe in an unusual and gruesome

13:55

manner. Andrew Curry is a contributing

13:57

correspondent for science. why

14:00

it might be sacrificed, why we might be

14:02

part of a ritual and why we think

14:05

these deaths are connected. Hi Andrew, welcome back

14:07

to the podcast. Thank you. So

14:09

how this paper got started or how someone

14:11

decided to take a closer look at these

14:14

deaths is kind of an unusual story

14:16

as well. Can we start there? Sure. The

14:20

lead author on the paper is a forensic

14:22

anthropologist in France who 40 years ago

14:26

as a younger forensic anthropologist in France

14:28

was excavating a site

14:30

that was built about 3500 BC

14:35

and he found three really unusually placed

14:37

bodies in what looked like a

14:39

grain storage pit. The two of

14:41

them were in a bizarre position and

14:44

at the time he sort of wrote

14:46

it off as as unique or you

14:48

know just something odd and

14:50

then later just just a few years

14:52

ago he told me he was

14:55

reading a paper about Italian

14:57

mafia killings and

15:00

he recognized the position of the bodies

15:03

from this Neolithic grave he had excavated

15:05

40 years before and

15:08

he he took the opportunity to look

15:10

through the literature and he found a

15:13

number of other similar positions

15:15

at similar sites all across

15:17

Europe from around the same

15:19

time. Wow. Let's get

15:21

into what exactly this method of killing

15:24

was that he suspected was going on

15:26

so far in the past. Yeah I have

15:28

to say you know I read a lot

15:30

of archaeology papers and this one was a

15:33

hard read. Yeah. Basically a rope

15:35

is tied around the throat and then the other end

15:37

of the rope is tied around your ankles. Victims

15:39

are placed on their stomach and

15:41

the weight of your legs strangles

15:44

you over the

15:46

course of a few minutes. You can't hold that position

15:49

for too long and yeah

15:51

so it's sort of a torturous way to die

15:54

that I guess is used by the Italian mafia

15:56

when they really want to make a statement. I

15:58

was going to say you know we might... suspect why

16:00

the mafia would do this, but what do researchers

16:02

think might have been the reason for doing this

16:05

5500 BCE? It's hard to say

16:08

why this particular position or why

16:10

they needed to subject people to

16:12

this. The author and his co-authors

16:15

suggested the societies at the time,

16:17

these are all farmers, these

16:19

are some of the first farmers in Europe

16:22

and something common to farming societies

16:24

is sacrificing to the gods because

16:26

these are sort of forces that

16:28

you depend on completely, the rain

16:30

and the sun, the weather,

16:33

and so sacrificing something

16:35

important, animals or even

16:37

people might be a way to try

16:39

and get those forces on your side.

16:41

But it's hard to know why that

16:43

style of

16:45

killing was a more powerful symbol or

16:48

was so common. Another archaeologist

16:50

I talked to said, it's a little hard

16:52

to say that it was symbolic. It might

16:54

have been, you know, that there's a limited

16:57

number of ways of killing people. There are

16:59

other kinds of human sacrifice that also take

17:01

place at time. How

17:03

many sites are we talking about here? They found 15 sites

17:06

where they were sure that this asphyxiation

17:09

or strangulation was involved and

17:11

I think 20 bodies and

17:14

the sites range from Bohemia, so sort

17:16

of modern day Czech Republic all the

17:18

way to northern Spain. And on

17:20

the one hand, that seems like a lot, but on the

17:22

other hand, 15 over

17:25

2000 years. Yeah. Yeah, it's

17:27

hard to say that that's

17:29

a universal phenomenon. Are

17:31

there any suggestions for why it might

17:33

have lasted so long or been, you

17:36

know, spread so far? The authors think that there was

17:38

a common belief system that

17:40

incorporated this position or this kind

17:42

of sacrifice into it. The comparison

17:44

he made was that in the

17:46

middle ages, you have all kinds

17:48

of different cultures in Europe who

17:50

speak different languages and eat different

17:52

foods and live in different places

17:54

over the course of hundreds or

17:56

even thousand years, but they

17:59

all would have recognized that. the significance

18:01

of the crucifix. So

18:03

maybe this is something symbolic that

18:05

different cultures share and

18:08

we just can't see exactly what

18:10

it meant to them. Yeah, there's a lot

18:12

of pieces that need to be filled

18:14

in because right now we have

18:16

body position and it's

18:19

not easy to tell if these people

18:21

even died from this, right? Because they

18:23

could have been positioned this way after

18:25

their death. It's super interesting, this is

18:27

something that comes up in the mafia

18:29

killings too. Sometimes

18:31

people are killed before and then put

18:34

in this position and because it's strangulation,

18:36

it doesn't leave any marks on the

18:38

bones like other forms of violence where

18:40

your skull is crushed or your bones

18:42

are nicked by arrowheads. So

18:45

really all we have to go on

18:47

is the position and it's

18:49

hard to know what happened in those last moments

18:52

or if they were indeed

18:54

alive. I guess the next

18:56

step is to look for not necessarily

18:58

more deaths like this but maybe some

19:00

kind of other evidence that this was

19:02

ritualistic or it was a sacrifice or

19:05

what kind of underpins the connection

19:07

between the different sites. Yeah, and

19:09

they try to find sites that

19:11

it's not just the position of

19:13

the bodies but also are

19:16

there other sites where it's clear that

19:18

there was a larger ceremony taking place

19:20

or at some

19:22

of these sites there was a

19:24

ditch with openings oriented towards the

19:27

solstice. So are

19:29

there also across cultures commonalities

19:31

that go beyond the position of the

19:33

bodies, also some sort of common element

19:36

in the rest of the ceremony? Because

19:38

it is, you know, 2000 years although

19:40

oral traditions do survive that long, it's

19:43

a very long time and it is

19:45

a huge span of geography. So

19:47

the way you end the story is great. So

19:49

whatever was happening here, it

19:52

basically, as far as, you know, went

19:54

out of style right around the emergence

19:56

of things like Stonehenge. Yes, so sort

19:58

of 3000 years. people

20:02

start doing something else. They

20:04

organize society differently. They're still farming,

20:06

but instead of these sacrifice

20:09

sites or whatever they may be,

20:12

they start getting people together to

20:14

move big stones and make tombs

20:17

and monuments and hinges

20:19

across France and eventually

20:21

England. And

20:24

this kind of sacrifice behind, thankfully.

20:28

For real. I feel like the hinges are

20:30

still pretty mysterious. And we know, have known

20:32

about them for a lot longer. So, I

20:34

mean, I was surprised that this sacrifice

20:38

might leave us with some unanswered questions

20:41

for quite a long time. Yeah, these aren't

20:43

dramatic sites to look at. They're pits in

20:45

the ground with a few people in them.

20:47

And it takes a really careful excavation

20:50

to record the physicians of the

20:52

bones in enough detail that a

20:55

forensic anthropologist can reconstruct a

20:57

death many millennia later. All

21:00

right. Thank you so much, Andrew. Thank you. Andrew

21:02

Curry is a contributing correspondent based in

21:04

Germany. You can find a link to the

21:07

story and a related science advances article, the

21:09

science.org/podcast. Don't

21:12

touch that dial. Up next, I talk

21:14

with researcher Eric Nelson about how viruses

21:16

hunt bacteria in our guts, like

21:19

lions hunt gazelles on the Savannah.

21:28

In areas without access to clean

21:31

water, cholera can become a problem.

21:33

The bacteria that cause this disease

21:35

gets into people from contaminated water.

21:38

Cholera affects over 1 million

21:40

people a year, killing more

21:42

than 100,000. It kills

21:45

through, we'll just say, severe

21:47

dehydration. Most people are able

21:49

to recover through hydration therapies, but not

21:51

always. And antibiotics are

21:54

sometimes needed. Like most

21:56

bacterial infections, there's a risk that the

21:58

cholera bacteria will evolve. involve defenses

22:00

against antibiotics over time and

22:03

become more difficult to treat. But

22:06

the color of bacteria is actually fighting

22:08

a war on two fronts against the

22:10

antibiotics used to treat it and

22:13

against a virus that infects and kills

22:15

the bacteria inside the human body. This

22:18

Week in Science, Eric Nelson and colleagues

22:20

write about this balance between bacteria, antibiotics,

22:23

and a virus. Hi Eric,

22:26

welcome to the Science Podcast. How

22:28

nice to be here. Thank you. Great.

22:31

So this virus that attacks the cholera bacteria,

22:33

it's called a phage. These are the viruses

22:35

that specifically target bacteria.

22:38

And it's been known about for a

22:40

really long time. I saw in your

22:42

paper a reference to people tried to

22:44

use this phage to cure cholera like

22:46

a hundred years ago. That's

22:48

correct. And many of

22:51

the discoveries that were made back

22:53

then were kind of left in some ways

22:55

incomplete because they didn't have the technology and skills

22:57

and insights that we have today. And

22:59

sometimes I feel like I'm just riding on the

23:01

coattails of work that was done a hundred years

23:04

ago. That's pretty amazing. I

23:06

guess they weren't sequencing the genomes of these different

23:08

bacteria and phage and trying to figure out how

23:10

they've changed over time. But we can do that

23:12

now. There's a few ways to treat cholera. As

23:15

I mentioned, hydration, antibiotics, but the phage is not

23:17

one of them at this point. This is not

23:19

something where you can go get like a

23:21

phage treatment. It's not currently available,

23:24

but like we said, there were,

23:26

I don't know how to say proto

23:28

or some of the original kind of

23:30

randomized control trials run back in the

23:32

20s and early 30s that showed 50%

23:35

reductions in mortality when you treated

23:37

a patient with a cute cholera with a

23:39

phage cocktail. That predated the

23:41

discovery of penicillin. And at that time, it

23:43

was amazing. You could have a bacterial infection

23:45

that you could treat with something that would

23:48

mitigate morbidity and mortality. And then as antibiotics

23:50

came on board, it kind of dropped away.

23:52

And teams have tried to keep that idea

23:54

alive. And then I think

23:56

in that era of antimicrobial resistance, it's come

23:58

back in the vogue. Yeah. How

24:01

do you know someone has cholera? Is

24:03

it hard to test for this? Well,

24:06

it depends. And I'll just say that I

24:09

am very humble today because I'm representing

24:11

two other teams. You have a

24:13

group of clinical trialists in Bangladesh led by

24:15

Dr. Khan at the International Center for Diarrheal

24:18

Disease Research. And then you have Jesse Shapiro

24:20

and Naima Madi at McGill. They're the computationalists

24:22

and I kind of sit in the in-between

24:24

as a microbiologist. You know, I can

24:26

play the hat of the pediatrician or the microbiologist or

24:29

the clinical trialists. But you would

24:31

think that in this era, you could identify

24:33

someone with cholera straight off. Yeah. But actually,

24:35

it depends. If you're in a place where

24:37

people are immunologically naive to cholera like they

24:40

were in 2010 in Haiti or in Zimbabwe

24:42

in 2008, the symptoms are not subtle.

24:47

It's perfuse watery diarrhea that

24:49

can kill, you know, in 18, 24 hours

24:51

after consumption of

24:53

bad water. If you're in a place like

24:56

Bangladesh that's endemic for the disease, the population

24:58

has a lot of immunological memory. And

25:01

the number of patients that are symptomatic

25:03

versus asymptomatic might be very dramatic.

25:05

And actually, in that context, it might be

25:07

quite hard to diagnose because there might be

25:10

very subtle findings. So then

25:12

you have to go to like a biochemical test or

25:14

some kind of culture. Well, in practice, cholera

25:16

hits some of the most kind of vulnerable

25:18

forest populations in the world. And so access

25:21

to a laboratory or even a rapid diagnostic

25:23

test can be really hard to come by.

25:25

Yeah. And so often, it's just a clinical

25:27

acumen, knowing your epidemiologic context in

25:29

that space. You know, not on this paper

25:32

is, you know, a discussion around why do

25:34

rapid diagnostic tests are kind of lateral flow

25:36

cell kind of like pregnancy tests, but in

25:38

this case for cholera, why

25:40

do they work sometimes really well? And

25:42

other times, they fail terribly. We get

25:45

at that question of sometimes phages, sometimes

25:47

antibiotics make those tests less effective. So

25:49

in practice, it's often just clinical acumen.

25:52

Let's move over to the clinical trial portion

25:54

of this. So your partners in Bangladesh,

25:56

they collected data from, I guess

25:59

we'll say potential cholera patients,

26:01

what were they looking for? Who did

26:04

they recruit and what kind of data did they

26:06

collect? It began as really a clinical question. This

26:08

is one of these kind of like, instead of

26:10

being bench to bedside, this is one of these

26:12

bedside to bench stories where a good

26:15

friend and colleague of mine, Dr. Kahn and

26:17

I, we ran this cluster randomized control trial

26:19

at 10 different government hospitals across

26:22

Bangladesh. And in that study,

26:24

we were asking if we built

26:26

digital tools to help doctors better

26:28

assess dehydration, could we look at

26:30

decreased rates of antibiotic usage and

26:33

improved rehydration? And so Dr. Kahn collected

26:35

samples in these sites. And I'll just

26:37

say that one of the things that

26:39

we focus on is how the samples

26:42

are collected, because where we

26:44

work, often there's no electricity and upwards of

26:46

10% of like a phage genome is nucleases.

26:48

So they shred the host microbe very

26:51

quickly. And so you might have

26:53

false negatives in your research. So we actually

26:55

preserve the samples with a reagent that doesn't

26:57

require a cold chain. But then downstream, the

26:59

research could find things that maybe other teams

27:01

might have missed. So you're saying that

27:03

if the bacteria was infected with a phage, then

27:06

it would, it would destroy the bacteria

27:08

in such a way that you wouldn't even really

27:10

be able to tell it had been there. Yeah,

27:12

I mean, for the microbiologist listening, it's hard to

27:14

believe that a phage could nuke the host bacterial

27:16

genome in such a way that even PCR couldn't

27:18

find it. Yeah. But that's

27:20

what we've kind of found over the years. So like

27:22

going back to your question of diagnosis, we have these

27:24

situations where a patient looks like they have cholera. You

27:27

do culture, you do rapid tests, you do

27:29

PCR for the pathogen, you can't find it.

27:31

And then if you switch around and look

27:33

for the virus that's eating the pathogen, you

27:36

can find the disease. How common is

27:38

this phage? Does everybody who you

27:40

looked at in Bangladesh, do they have this

27:42

phage? And in those places where you said

27:45

where it kind of was a naive population,

27:47

like in Haiti, did they also have

27:49

this phage? I'll do the second

27:51

one first. So okay, I know it's

27:53

political, but the evidence is very strong

27:55

that a UMPs keeper from

27:58

Southeast Asia flew to Haiti. with

28:00

cholera and contaminated a

28:02

river north of Port-au-Prince. But

28:05

what that person forgot to bring on their trip

28:07

was the primary phage we're setting in this paper.

28:09

Whereas if you look at, it depends on

28:12

when an outbreak you're looking, but

28:14

generally you find about half the patients have

28:16

these phages and half don't, and that ratio

28:18

is going to change over the arc of

28:20

an outbreak. You're going to see an increase

28:22

in phage because they're like, yum food, and you're

28:24

just going to get more and more phage. It's

28:27

like this idea that outbreaks spark

28:30

and spread exponentially because cholera is

28:32

coming out of the patient hyper-infectious.

28:35

And then they're expanding at a rapid rate,

28:37

and then the phage, like you said, are

28:39

kind of viewing the cholera as food, and

28:42

they're going to begin expanding later in the

28:44

outbreak. And one idea is that

28:46

the outbreaks actually collapse because the

28:48

phages finally get ahead of its

28:50

food source being the cholera. That's starting to sound

28:52

like what I hear about happening in the

28:54

ocean, where there are all these ocean microbes

28:56

being killed on the daily by phage. So

28:59

it's actually my background is marine microbiology.

29:02

And whenever the clinicians are struggling with

29:04

the literature on the human side, I

29:07

point them towards the marine micro-icide because

29:09

that literature is so strong. It's

29:11

such an important cycle for the ocean, for

29:14

food webs, for global carbon. It's

29:16

really just amazing that it's happening on

29:18

this micro-scale, I guess, in the human

29:20

body. And the math coming from

29:22

that literature is at play in

29:25

our guts with cholera and phages. And

29:27

there's much more similarity than differences. Just

29:30

in the human infectious disease space,

29:32

especially in the GI space, there's

29:34

just been less opportunities to study

29:36

it at scale. And it's

29:38

just that cholera is such a scaled organism.

29:40

Like at our center in Dhaka, we have

29:43

1,000 to 2,000 cholera patients admitted per day.

29:48

It's very hard to manage clinically,

29:50

but from a scientific perspective, there's

29:52

an incredible amount of science to be done in

29:54

a short time that you can't do with other

29:57

diseases. Like you talked about the

29:59

phage destroying. the bacteria making

30:01

it hard to, you know, detect.

30:03

But you also had a lot

30:05

of concerns about covert antibiotic use.

30:07

So it wasn't prescribed to people, but

30:09

there was a chance that they also had that going

30:11

on when they came in. So sadly, you

30:13

know, we're a polluted world when it comes

30:15

to antibiotics. And if you ask

30:18

our average patient in Bangladesh, when they come

30:20

in, did they take a drug? Maybe

30:22

half of them will say yes. But if

30:24

you do mass spec, nearly all of them

30:26

have drug and usually it's two or more.

30:29

And we haven't built that into our experiments

30:31

historically. And now in this

30:33

paper, we're pulling in phages, which historically

30:35

were forgotten a bit. We're pulling in

30:37

truth on antibiotic exposure with mass spec.

30:39

And then, you know, I think of

30:41

this as almost like the Swedish chef,

30:44

where you put it all in the pot, and

30:47

you see what you get at the end of the day. So you wanted to

30:49

know how much bacteria they have, how much phage they

30:51

have, and then if they have taken antibiotics, and then

30:53

you can sort out and kind of see the fate

30:56

of their dehydration or their like clinical

30:58

progress based on those variables. Is that

31:01

what you were looking at? Yeah,

31:03

that was the kind of grand hypothesis,

31:05

which is if you look at two

31:07

patients that seemingly are identical, why is

31:09

one in shock without a distal pulse?

31:11

And why is one having mild dehydration

31:14

sitting upright, eating a banana and watching

31:16

TV? What's biologically going on there? So

31:18

in this experiment, we're asking, are phages

31:20

a determinant of that? Are antibiotics a

31:22

determinant of that? And what's the interaction

31:24

of those? Say you have

31:26

a patient that has antibiotics and

31:28

phage, are they even better? Are

31:30

they the sitting up eating a banana people? Or

31:33

is it more fine grained than that? It's

31:35

always more complicated. Yeah. This is a hypothesis

31:37

that was on the table about 10 years

31:40

ago when we started these clinical trials. And

31:43

I thought it would be like

31:45

a drug detected, yes, no. If a detected,

31:47

yes, no. And what was the correlation with

31:49

severe disease? And after, I

31:51

don't know, I was like six months to

31:53

a year of analysis of was it detected

31:56

or not, we didn't really find anything. The

31:59

hypotheses weren't. sorting themselves out. And

32:01

then I read back into some older literature from

32:04

some of my heroes, and there's

32:06

some work that was done that said, don't

32:08

just think about was it detected or not,

32:10

what is the relationship between predator and prey

32:13

as almost like a biomarker of a readout? And

32:16

so we began looking at the data in

32:18

terms of ratio. And we had this idea

32:20

of thinking about effective predation was if

32:23

you have a lot of predator

32:25

being the phage with not a

32:27

lot of prey being the Vibrio

32:29

cholery, if that ratio is high

32:31

effective predation, was that the correlate

32:33

with mild dehydration? And then if

32:35

it was ineffective predation, having the

32:37

opposite, were those patients severe? And

32:39

once we flip that question into

32:41

a ratio and a biomarker question,

32:44

then the analysis kind of jumped off the

32:46

page within a day. It was pretty exciting.

32:49

That is it's very much like an

32:51

ecological perspective on what's happening, like

32:53

thinking about predator and prey ratios. That's

32:55

not usually something you think about happening in the gut, right? You

32:57

think about it out there on the savannah.

33:01

Be it Darwin's finches, or

33:03

gazelles and lions on the savannah,

33:05

or like you said, phytoplankton, the

33:07

ocean, the math is the same.

33:09

Yeah. And we think about 10

33:11

to 100 bacterial cells in our

33:13

gut, compared to our own cells,

33:17

but then the phages have 10 to 100 on

33:19

top of the bacterial cells. So that biology isn't

33:21

super well understood, but it's happening right now in

33:23

that chat with you. So you did see

33:25

this correlation then between your ratio

33:28

of predator to prey and

33:30

dehydration state. Once you were able to

33:32

get that number or that ratio out,

33:34

you were able to kind of make

33:36

predictions or better understand people's cases? That's

33:38

correct. So that was kind of the

33:40

first discovery, which was, once

33:42

we looked at things with ratios,

33:44

we could draw clear lines to

33:46

disease severity. And even if you

33:48

don't go beyond that first discovery,

33:51

it's really important because you can

33:53

use that discovery to think about

33:55

confounding in clinical trials, how

33:57

to think about not just building diagnostics, but

33:59

also... So true positive versus false

34:01

positives, true negatives versus false negatives

34:03

on the diagnostic side. And

34:06

also epidemiologically, like the numbers you gave

34:08

on disease burden are probably a huge

34:10

underestimation of true collar burden. And it's

34:13

just that we can build these things

34:15

into our either current suite of diagnostics,

34:17

or we can think about a future

34:19

where metagenomics can not only identify the

34:22

pathogen, but they can

34:24

actually predict the disease severity now and

34:26

in the future. And then I

34:28

think we're going to get to a place where you can

34:30

actually use the profile from the metagenome to

34:33

say, look, there's probably an antibiotic in

34:35

this patient that you don't know about

34:38

correct for that factor so that your clinical

34:40

decision and epidemiology is more spot on. I

34:42

also want to get to, you know, as I

34:45

mentioned before, this arms race idea that, you

34:47

know, antibiotics, you're worried about

34:49

microbes getting more and more resistant to

34:51

them. There's also a similar thing

34:53

that can happen with the phage where

34:56

the bacteria can evolve

34:59

and basically protect itself from

35:01

this virus. What did

35:03

you find out about that process in your study? That's

35:06

super exciting. So I'll just let the

35:08

listeners know that the whole phage

35:10

evolutionary piece came after we submitted

35:12

the paper. Was

35:15

it from a helpful reviewer, perhaps? It

35:17

was partly from the reviewer, but also

35:19

Naima Māori, the first author. She's

35:22

brilliant and usually you don't want to

35:24

go beyond what the reviewers ask you to do,

35:26

but she went beyond and we debated like, do

35:28

we include this in the paper or not? And

35:30

we just went for it. And

35:33

for those kind of evolutionary

35:35

biology nerds out there, there's

35:37

someone named Van Vailen, not

35:39

Van Halen. And

35:41

Van Vailen has this old theory

35:43

from like 1973 around something

35:46

called the Red Queen Hypothesis, which

35:48

is both the predator and prey have to

35:50

run just to stay in the same place. And

35:53

while the first part of the story was

35:56

if you have effective predation in which

35:58

you put the squeeze on. the

36:00

pathogen by the phages and you have

36:02

that ineffective predation, you have mild disease,

36:05

does the pathogen have increased genetic diversity?

36:07

That was kind of where we started.

36:09

And then Naima kind of flipped that

36:12

around and said, will it happen if

36:14

the predation is ineffective, will the squeeze

36:16

be on the phage particles and you'll

36:19

have increased genetic diversity? That's

36:21

the part that came actually after we submitted the paper

36:23

and she showed it. And so you really

36:26

close that loop in the Red Queen hypothesis

36:28

in a way that hasn't been shown very

36:30

often in human medicine. Wow. One

36:33

thing that you kind of started with was

36:35

that this is real. The Global Task Force

36:37

for Cholera Control, which is at the WHO,

36:39

that team there is dealing with nearly

36:41

30 countries that are battling large-scale cholera

36:43

outbreaks. And you know, a whole long list

36:46

of people have studied cholera for all

36:48

these years and you would think that

36:50

in this day and age we would be

36:52

doing a better job. But you have

36:54

those gaps in the science, gaps in

36:56

the clinical approach, and then challenges with

36:58

economics and leadership and war that

37:00

make this problem very real and present.

37:03

There's also like a clinical piece

37:05

which is, does anyone in the

37:07

US or developed world care about

37:09

cholera? Yeah, we should. Yeah, so

37:11

like you know my paycheck is

37:13

from the US taxpayers. Why should

37:15

the US taxpayer care about cholera

37:18

in Haiti or many other places? And

37:21

I would say we have a humanitarian obligation

37:23

there. But you could

37:25

also make a case that if you have a

37:28

urinary tract infection and you're on

37:30

University of Florida campus in our hospital, everything

37:33

that we just chatted about it's probably at

37:35

play in your bladder when you're taking a

37:37

drug, when you have E. coli in your

37:39

bladder, and when phages may or not be

37:41

there. And if a patient says,

37:44

oh, where are you going to look at

37:46

those drug concentrations and the phase dynamics? I'll

37:48

say, well, that's not even on the table

37:50

in terms of how we train clinicians or

37:52

how we approach things clinically. But it should

37:54

be now in the future.

37:56

So there might be all kinds of common

37:58

infections where the bacteria we... We are testing

38:00

for it, but it turns out there are

38:02

also phage that are targeting those bacteria, battling

38:05

it out inside of our bodies, and we

38:07

are not trying to detect that. And

38:10

as you mentioned, if there's a

38:12

phage involved, there could be, this

38:14

could be a confounder in all

38:16

kinds of infectious disease trials, you know,

38:18

not just for cholera, but for other

38:21

kinds of infections. Trials

38:23

are really expensive to run. Yeah. It's

38:26

a bummer if you get one of those kind

38:29

of 0.09 p-value studies and

38:31

you're like, oh, it sort of worked. But

38:33

then if you assayed for these phages and

38:36

then you went on to look for these

38:38

ratios and you did some math spec, and

38:40

suddenly you found a much more meaningful finding,

38:42

that's important. And as we try

38:45

to come with better suites of antibiotic regimens, we

38:47

need to build this into our

38:49

standard of practice. Thank you so much,

38:51

Eric. Thank you for your time. Eric

38:53

Nelson is an associate professor in the departments

38:55

of Pediatrics and Environmental and Global

38:58

Health and in the Emerging Pathogens

39:00

Institute at University of Florida. You

39:02

can find a link to the

39:04

paper we discussed at science.org/podcast. And

39:08

that concludes this edition of the Science Podcast.

39:11

If you have any comments or

39:13

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39:15

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39:25

This show was edited by me,

39:27

Sarah Krusty, and Kevin McLean. This

39:30

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39:32

Strategy, Jeffrey Cook Composed the

39:34

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39:36

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39:38

for joining us.