Ritual murders in the neolithic, why 2023 was so hot, and virus and bacteria battle in the gut

This episode dives into a mix of history, climate science, and medical microbiology, exploring Neolithic ritual murders, the impact of reduced air pollution on global warming, and the interaction between viruses, bacteria, and antibiotics in the gut.

1. Reductions in air pollution may paradoxically lead to higher global temperatures due to increased solar absorption caused by cleaner skies.
2. Ritual murders in Neolithic Europe may have had symbolic significance similar to other forms of human sacrifice known from the era, potentially linked to agricultural societies' dependence on favorable weather conditions.
3. The relationship between cholera bacteria and bacteriophages in the human gut represents a complex ecological interaction that could inform future treatments for antibiotic-resistant infections.
4. The episode explores how historical and current scientific insights can be interconnected, providing a broader understanding of human impact on the environment and each other.
5. The detailed discussion on each topic not only informs but also challenges listeners to think critically about the implications of scientific developments.

1. Climate Impact of Reduced Pollution

This chapter discusses how cleaner air leads to increased solar energy absorption at the Earth's surface, potentially accelerating global warming. Key insights are provided into the scientific mechanisms behind these changes. Sarah Crespi: "Cleaner skies are ironically leading to a warmer planet."

2. Neolithic Ritual Murders

Exploring ritualistic killings in Neolithic Europe, this segment compares these ancient practices to modern-day criminal methods, suggesting a deep-rooted cultural significance. Andrew Curry: "These ritual murders might have been a way to appease the gods."

3. Virus and Bacteria Battle in the Gut

Focusing on the interaction between cholera bacteria and bacteriophages, this chapter highlights the potential of using phages to treat bacterial infections in the gut. Eric Nelson: "Bacteriophages might play a crucial role in treating cholera in the future."

1. Support clean energy initiatives to mitigate the warming effects of cleaner skies.
2. Promote and support archaeology to understand historical human behaviors and their contexts.
3. Advocate for increased research into bacteriophage therapy to combat antibiotic-resistant bacteria.
4. Stay informed about environmental changes and their impact on public health.
5. Engage with scientific content to foster a well-rounded understanding of complex issues.

A different source of global warming, signs of a continentwide tradition of human sacrifice, and a virus that attacks the cholera bacteria

First up on the show this week, clearer skies might be accelerating global warming. Staff Writer Paul Voosen joins host Sarah Crespi to discuss how as air pollution is cleaned up, climate models need to consider the decrease in the planet’s reflectivity. Less reflectivity means Earth is absorbing more energy from the Sun and increased temps.

Also from the news team this week, we hear about how bones from across Europe suggest recurring Stone Age ritual killings. Contributing Correspondent Andrew Curry talks about how a method of murder used by the Italian Mafia today may have been used in sacrifices by early farmers, from Poland to the Iberian Peninsula.

Finally, Eric Nelson, an associate professor at the University of Florida’s Emerging Pathogens Institute, joins Sarah to talk about an infectious bacteria that’s fighting on two fronts. The bacterium that causes cholera—Vibrio cholerae—can be killed off with antibiotics but at the same time, it is hunted by a phage virus living inside the human gut. In a paper published in Science, Nelson and colleagues describe how we should think about phage as predator and bacteria as prey, in the savanna of our intestines. The ratio of predator to prey turns out to be important for the course of cholera infections.

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Sarah Crespi, Paul Voosen, Andrew Curry, Eric Nelson

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Sarah Crespi

This podcast is supported by the Icon School of Medicine at Mount Sinai, one of America's leading medical research schools. How will advances in artificial intelligence transform medical research and medical care? To find out, we invite you to read a special supplement to science magazine prepared by Icon Mount Sinai in partnership with Science. Just visit our website@science.org, and search for frontiers of medical research Artificial Intelligence on May 1 and May 2, Icon Mount Sinai and the New York Academy of Sciences will be convening a major symposium in New York City on the new wave of AI in healthcare. For more information and to register, please visit events dot nyas.org aihealth.

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This is the science podcast for April 19, 2024. I'm Sarah Crespi. First up on the show, staff writer Paul Vusin is here to talk about how reductions in air pollution may lead to a warmer planet. Next, I'm joined by contributing correspondent Andrew Curry. We're going to discuss what what appear to be ritual killings carried out in Neolithic Europe.

We talk about how these gruesome deaths actually resemble some modern day mafia killings. Finally, we have researcher Eric Nelson to talk about how cholera is fighting a war on two fronts. Actually, this is the cholera bacteria, which can be killed by antibiotics, but it's also hunted inside the gut by a bacteria killing virus. It turns out the dynamics between the virus, the bacteria and antibiotics are important to understanding the course of the disease.

This past year, 2023 was the hottest on record, and these high temps support the idea that global warming, climate change, is accelerating at an unexpected rate. This week in Science, staff writer Paul Vusin wrote about a possible contributing factor. Cleaner skies leading to more absorption of solar energy at the surface. Hi, Paul. Hi.

Welcome back to the podcast. Thank you. I found this a little confusing the first time I heard about it. You know, isn't absorbing radiation from the sun kind of the main driver for global warming? How is what we're talking about today something different?

Paul Voosen

There's this thing called the albedo of the earth, and that's the amount of light that we reflect back into space. And over the past couple of decades, there's these instruments in space that have been monitoring. They look at both the energy being reflected and then the kind of heat being given off by the planet. Tally those together compared to the energy we know that's coming from the sun, and you get the amount of excess energy in the planet. And over this time, especially in the last decade, the planet has became less reflective.

So more sun is not being reflected off before it hits the surface of the earth. So at the ground level, essentially, it's getting sunnier. This is something I've heard about before. When we talk about shrinking of the ice caps, that means we'll have less reflectance. But this is a more general process, like, over the whole surface of the.

Planet, there are a lot of different things that can contribute. It's not just cleaner skies, it's clearer skies, really. One big part of this is atmospheric pollution, a decline and atmospheric pollution that would otherwise be reflecting light. But that's not necessarily the whole story of this. There's a lot of this that right now is just a big mystery.

Climate scientists don't understand why it's becoming less reflective. It could be other changes with the clouds that are not tied to pollution, or it could be shifting circulation, like air, ocean circulations, things like this that are just not quite understood yet. Pollutants would have contributed to darker skies or less clear skies, because there's, like, particulates and aerosols and that, you know, shines light back into the sun. One of the primary things here is sulfate aerosols. So you have sulfur dioxide comes out of power plants, dirty power plants, and create these little reflective aerosols that shoot light back.

They also interact with clouds and cause clouds to get brighter, give them little cloud nuclei to make them more reflective or last longer than the atmosphere. Just how powerful both of these are is another big uncertainty in climate. And what about the timing? You said this is something that's been observed a lot more in the last decade, but we've been cleaning up the atmosphere for some time in various parts of the planet, not regularly around the whole sphere. In some ways, this is expected, at least part of it, not unexpected.

We've known that curbing pollution, which is a good thing. Yeah, let's causes lots of deaths. You don't want to keep pollution just to limit warming. Far worse a problem than warming, right? Yeah.

This is built into climate models to extent that declining pollution will see warming ramp up. And even in the predictions of climate models, warming does ramp up, accelerate some because these aerosols are going down now. This happened in the seventies and going onward. There's also work that suggests that when you clean up that pollution, especially in kind of really dirty places, it can take a couple of decades to actually really make a difference, which is something somewhat counterintuitive. You think, oh, they stopped the pollution, then things should change right away.

But some clouds are most sensitive to the first bits of pollution they get to. As you're ramping down the pollution, the clouds might not necessarily be changing that much until you really get low. You know, some of this, what we're seeing now could be tied to reductions from the 1990s. Really. There's kind of a lot of unknowns here.

Sarah Crespi

But one thing that I was wondering about is, you know, we're talking about this increased energy absorption by the planet. How does that compare to what anthropogenic gases are doing, like, the global warming part of what's happening? I'm really trying to tease apart this difference between what we're talking about here, like clear skies, this increased absorption and anthropogenic climate change from greenhouse gases. Like, how do these things compare to each other? It can be potentially large for the short term.

Paul Voosen

Global warming keeps getting bigger year after year. That's the kind of inexorable CO2 rising in the atmosphere. It becomes more and more powerful. But over, say, this past 20 years, this modeling study looked at the increased energy in the system over that time. So from 2000 to 2019, you have x amount of energy, new energy in the system, maybe 40% of that.

It came from a decline in reflectivity and potentially driven by this reduction in pollution. The other part would be increasing greenhouse gases mostly. Oh, wow. Okay. Do we expect this increase in energy absorption to kind of level out or be reversed while the greenhouse gas effect just keeps ramping up?

This is one of the big questions. This is like a big, difficult to grasp question in climate science, because if this is just driven by declining pollution, right, then, okay, we get there and then it's not going to keep happening. Right. You can only get so clean. It would be lovely to have clear, clean skies.

Right. It's a short term thing. It's really unveiling some of the warming that we've blocked before. But if there's something else going on which climate models can't really explain everything, it seems right now, like, if some clouds are changing in some ways, that could continue, and it's just totally not understood. There are reasons to think that there is something else going on, because with these instruments in space called Ceres, they see the reflectivity of the planet declining in both hemispheres, like northern southern hemisphere, whereas pollution has really dropped in the northern hemisphere.

So, like, what's going on down in the southern hemisphere? Right. It's a big question. The climate models only go up through 2019, so something different might have been happening in the past few years and we wouldn't be able to tell. Yeah, climate models projections obviously go out for hundreds of years.

Sarah Crespi

Yeah, I was going to say. But when you are trying to use real world data to constrain what they're doing or understand kind of near term, you do things like you put in the actual sea surface temperatures that were experienced over that time, so you can kind of recreate the weather a bit more closely or use real world data for how much pollution there was. And that can help you actually figure out what's going on versus it just going freely and creating some earth that's kind of like the earth, but not. Quite like the earth. There's this big bureaucracy to climate modeling that revolves around the UN climate reports, so they put the plans together.

Paul Voosen

The latest generation was finalized in 2017. The plans for it, and just takes time to get the new data and update all this. But one thing is people are pushing that we need to do this more frequently to understand near term mysteries that might arise. Speaking of continuing modeling, continuing measuring, these Siri satellites, these instruments up on the satellites, they're not going to be around forever. Are we going to be able to keep observing this change in energy on the earth's surface?

It's quite possible there could be a big gap. So right now, there are six total instruments. Four of them are on these workhorse, amazing satellites that have been up for 20 years, for more than 20 years, but their orbits are now drifting and they're going to go kaput in a couple more years. Even now, it's not getting the same type of data because their orbits are drifting. So it's.

They're essentially not that useful for the climate record. Fifth satellite, it's a weather satellite that's going to go out of service likely in the next few years. And so the last instrument is on kind of a flagship weather satellite for the US. And, you know, it should keep going till the successor comes up, maybe 2028, but it's a single point of failure. So some bit goes wrong or it gets struck by radiation and then that record goes silent.

And these are such small, so, like, the amount of energy coming in and leaving the planet, it's like huge. And global warming is, you know, 1% signal within that. So you need to have this trend continuing to be able to like, ease out anything. So a gap here is more damaging than some other satellite records, I'd say. Thanks so much for talking with me, Paul.

Oh, yeah, no problem. Paul Vuson is a staff writer for Science. You can find links to the stories we discussed@science.org. Podcast stay tuned for a chat with me and Andrew Curry about human sacrifice in neolithic Europe.

Sarah Crespi

Researchers at Queen's University Belfast translate research into action and make sense of a rapidly changing world. They keep up with technological, societal and economic advances and drive change through collaboration and real world partnerships. Their research leads to critical breakthroughs in areas such as green technology, food and agricultural sustainability, peace building and healthcare. Queens University Belfast Network of international researchers has a reputation for global excellence. Over 99% of their research was assessed as world leading or internationally excellent.

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This week's episode is brought to you in part by the Eppendorf and Science Prize for Neurobiology. Are you or one of your colleagues doing great neuroscience? If so, then we encourage you to apply for the prestigious Eppendorf and Science Prize for Neurobiology, an international prize which honors young scientists for outstanding neurobiological research based on methods of molecular cellular systems or organismic biology. Submissions are due June 15. Visit science.org eppendorf to apply today.

Okay, just a quick warning for listeners that might be sensitive to descriptions of violence. This is going to be a little bit graphic. We're going to talk about a way of murdering people. This story is about what looks like ritualistic killings of people in neolithic Europe in an unusual and gruesome manner. Andrew Curry is a contributing correspondent for science.

He wrote about why it might be sacrifice, why it might be part of a ritual, and why we think these deaths are connected. Hi Andrew. Welcome back to the podcast. Hi. Thank you.

So how this paper got started, or how someone decided to take a closer look at these deaths is kind of an unusual story. As well. Can we start there? Sure. The lead author on the paper is a forensic anthropologist in France who 40 years ago, as a younger forensic anthropologist in France, was excavating a site that was built about 3500 bc.

Andrew Curry

And he found three really unusually placed bodies in what looked like a grain storage pit. Two of them were in a bizarre position. And at the time he sort of wrote it off as unique or just something odd. And then later, just a few years ago, he told me he was reading a paper about italian mafia killings and he recognized the position of the bodies from this neolithic grave he had excavated 40 years before. And he took the opportunity to look through the literature and he found a number of other similar positions at similar sites all across Europe from around the same time.

Sarah Crespi

Wow. Let's get into what exactly this method of killing was that he suspected was going on so far in the past. Yeah, I have to say I read a lot of archaeology papers and this one was a hard read. Yeah. Basically, a rope is tied around the throat and then the other end of the rope is tied around your ankles.

Andrew Curry

Victims are placed on their stomach and the weight of your legs strangles you over the course of a few minutes. You can't hold that position for too long and, yeah, so it's sort of a torturous way to die that, I guess is used by the italian mafia when they really want to make a statement. I was going to say we might suspect why the mafia would do this, but what do researchers think might have been the reason for doing this, 5500 bce? It's hard to say why this particular position or why they needed to subject people to this. The author and his co author suggested that societies at the time, these are all farmers.

These are some of the first farmers in Europe. And something common to farming societies is sacrificing to the gods, because these are sort of forces that you depend on completely, the rain and the sun, the weather. And so sacrificing something important, animals or even people, might be a way to try and get those forces on your side. But it's hard to know why that style of killing was a more powerful symbol or was so common. Another archaeologist I talked to said, it's a little hard to say that it was symbolic.

It might have been, you know that there's a limited number of ways of killing people. There are other kinds of human sacrifice that also take place at the time. It is striking. How many sites are we talking about here? They found 15 sites where they were sure that this asphyxiation, or strangulation was involved and I think 20 bodies.

And the sites range from Bohemia. So sort of modern day Czech Republic all the way to northern Spain. And on the one hand that seems like a lot, but on the other hand, 15 over 2000 years. Yeah, yeah. It's hard to say that that's a universal phenomenon.

Sarah Crespi

Are there any suggestions for why it might have lasted so long or been spread so far? The authors think that there was a common belief system that incorporated this position or this kind of sacrifice into it. The comparison he made was that in the middle ages you have all kinds of different cultures in Europe who speak different languages and eat different foods and live in different places over the course of hundreds or even thousand years. But they all would have recognized the significance of the crucifix. So maybe this is something symbolic that different cultures share and we just can't see exactly what it meant to them.

Yeah, there's a lot of pieces that need to be filled in because right now we have body position and it's not easy to tell if these people even died from this because they could have. Could they have been positioned this way after their death? It's super interesting. This is something that comes up in the mafia killings too. Sometimes people are killed before and then put in this position.

Andrew Curry

And because it's strangulation, it doesn't leave any marks on the bones like other forms of violence where your skull is crushed or your bones are nicked by arrowheads. So really all we have to go on is the position. And it's hard to know what happened in those last moments or if they were indeed alive. I guess the next step is to look for not necessarily more deaths like this, but maybe some kind of other evidence that this was ritualistic or it was a sacrifice or what kind of underpins the connection between the different sites. Yeah, and they try to find sites that it's not just the position of the bodies, but also are there other sites where it's clear that there was a larger ceremony taking place?

Or at some of these sites there was a ditch with openings oriented towards the solstice. So are there also, across cultures, commonalities that go beyond the position of the bodies? Also some sort of common element in the rest of the ceremony, because it is 2000 years. Although oral traditions do survive that long, it's a very long time and it is a huge span of geography. So the way you end the story is great.

Sarah Crespi

So whatever was happening here, it basically, as far as we know, went out of stack right around the emergence of things like Stonehenge yeah. So sort of 3500 bc, people start doing something else. They organize society differently. They're still farming, but instead of these sacrifice sites or whatever they may be, they start getting people together to move big stones and make tombs and monuments and hinges across France and eventually England. And they leave this kind of sacrifice behind, thankfully.

For real. I feel like the henges are still pretty mysterious, and we have known about them for a lot longer. So, I mean, it's not surprised that this sacrifice might leave us with some unanswered questions for quite a long time. Yeah, these aren't dramatic sites to look at. There are pits in the ground with a few people in them, and it takes a really careful excavation to record the positions of the bones in enough detail that a forensic anthropologist can reconstruct to death many millennia later.

All right, thank you so much, Andrew. Thank you. Andrew Currie is a contributing correspondent based in Germany. You can find a link to the story and a related science advances article in Science.org podcast. Don't touch that dial.

Up next, I talk with researcher Eric Nelson about how viruses hunt bacteria in our guts, like lions hunt gazelles on the savannah in areas without access to clean water, cholera can become a problem. The bacteria that cause this disease gets into people from contaminated water. Cholera affects over 1 million people a year, killing more than 100,000. It kills through, we'll just say, severe dehydration. Most people are able to recover through hydration therapies, but not always.

And antibiotics are sometimes needed. Like most bacterial infections, there's a risk that the cholera bacteria will evolve defenses against antibiotics over time and become more difficult to treat. But the cholera bacteria is actually fighting a war on two fronts, against the antibiotics used to treat it and against a virus that infects and kills the bacteria inside the human body. This week in science, Eric Nelson and colleagues write about this balance between bacteria, antibiotics, and a virus. Hi, Eric.

Welcome to the science podcast. Nice to be here. Thank you. Great. So this virus that attacks the cholera bacteria, it's called a phage.

These are the viruses that specifically target bacteria, and it's been known about for a really long time. I saw in your paper a reference to people tried to use this phage to cure cholera, like a hundred years ago. That's correct. And many of the discoveries that were made back then were kind of left in some ways incomplete because they didn't have the technology and skills and insights that we have today. And sometimes I feel like I'm just riding on the coattails of work that was done 100 years ago.

That's pretty amazing. I guess they weren't sequencing the genomes of these different bacteria and phage and trying to figure out how they've changed over time, but we can do that now. There's a few ways to treat cholera, as I mentioned, hydration antibiotics, but the phage is not one of them at this point. This is not something where you can go get like a phage treatment. It's not currently available.

Paul Voosen

But like we said, there were. I don't know if you say proto or some of the original kind of randomized control trials run back in the twenties and early thirties that showed 50% reductions in mortality. When you treated a patient with acute cholera with a phage cocktail that predated the discovery of penicillin. And at that time, it was amazing. You could have a bacterial infection that you could treat with something that would mitigate morbidity, mortality.

And then as antibiotics came on board, it kind of dropped away. And teams have tried to keep that idea alive. And then I think in that era of antimicrobial resistance, it's come back in the vogue. Yeah. How do you know someone has cholera?

Sarah Crespi

Is it hard to test for this? Well, it depends. And ill just say that I am very humble today because Im representing two other teams. You have a group of clinical trialists in Bangladesh led by doctor Khan at the International center for Diarrheal Disease Research. And then you have Jesse Shapiro and Naima Mahdi at McGill.

Paul Voosen

Theyre the computationalists. And I kind of sit in the in betweens as a microbiologist, you know, I can play the hat of the pediatrician or the microbiologist or the clinical trial is. But you would think that in this era, you could identify someone with cholera straight off. Yeah, but actually it depends. If you're in a place where people are immunologically naive to cholera, like they were in 2010 in Haiti or in Zimbabwe in 2008, the symptoms are not subtle.

It's profuse watery diarrhea that can kill, you know, in 1820, 4 hours after consumption of bad water. If you're in a place like Bangladesh that's endemic for the disease, the population has a lot of immunological memory, and the number of patients that are symptomatic versus asymptomatic might be very dramatic. And actually, in that context, it might be quite hard to diagnose because there might be very subtle findings. So then do you have to go to like, a biochemical test or some kind of culture? Well, in practice, cholera hits some of the most kind of vulnerable, poorest populations in the world.

And so access to a laboratory or even a rapid diagnostic test can be really hard to come by. And so often it's just a clinical acumen. Knowing your epidemiologic context in that space, not on this paper, is a discussion around why do rapid diagnostic tests are kind of lateral flow cell, kind of like pregnancy tests, but in this case for cholera, why do they work sometimes really well, and other times they fail terribly. We get at that question of sometimes phages, sometimes antibiotics make those tests less effective. So in practice, it's often just clinical acumen.

Sarah Crespi

Let's move over to the clinical trial portion of this. So your partners in Bangladesh, they collected data from, I guess we'll say, potential cholera patients. What were they looking for? Who do they recruit, and what kind of data do they collect? It began as a really a clinical question.

Paul Voosen

This is one of these kind of, like, instead of being benched to bedside, this is one of these bedside the bench stories where a good friend and colleague of mine, Doctor Khan, and I, we ran this cluster randomized control trial at ten different government hospitals across Bangladesh. And in that study, we were asking if we built digital tools to help doctors better assess dehydration, could we look at decreased rates of antibiotic usage and improved rehydration? Doctor Kahn collected samples in these sites, and ill just say that one of the things that we focus on is how the samples are collected, because where we work, often there's no electricity, and upwards of 10% of, like a phage genome is nucleases. So they shred the host microbe very quickly, and so you might have false negatives in your research. So we actually preserve the samples with a reagent that doesn't require a cold chain.

So then downstream, the research could find things that maybe other teams might have missed. So you're saying that if the bacteria was infected with a phage, then it would. It would destroy the bacteria in such a way that you wouldn't even really be able to tell it had been there? Yeah. I mean, for the microbiologists listening, it's hard to believe that a phage could nuke the host bacterial genome in such a way that even PCR couldn't find it.

Yeah, but that's what we've kind of found over the years. So, like, going back to your question of diagnosis, we have these situations where a patient looks like they have cholera. You do culture, you do rapid test, you do PCR for the pathogen, you can't find it, and then if you switch around and look for the virus that's eating the pathogen. You can find the disease. How common is this phage?

Sarah Crespi

Does everybody who you looked at in Bangladesh, did they have this phage? And in those places where you said where it kind of was a naive population, like in Haiti, did they also have this phage? I'll do the second one first. So, okay, I know it's political, but the evidence is very strong that a UN peacekeeper from Southeast Asia flew to Haiti with cholera and contaminated a river north of Port au Prince. But what that person forgot to bring on their trip was the primary phage we're setting in this paper.

Paul Voosen

Whereas if you look at it depends on when an outbreak you're looking. But generally we find about half the patients have these phages and half don't. And that ratio is going to change over the arc of an outbreak. You're going to see an increase in phage because they're like, yum. Food, and you're just going to get more and more phage.

There's this idea that outbreaks spark and spread exponentially, because cholera is coming out of the patient hyperinfectious, and then they're expanding at a rapid rate. And then the phage, like you said, are kind of viewing the cholera as food, and they're going to begin expanding later in the outbreak. And one idea is that the outbreaks actually collapse because the phages finally get ahead of its food source being the cholera. That's starting to sound like what I hear about happening in the ocean, where there are all these ocean microbes being killed on the daily by phage. So it's actually, my background is marine microbiology.

And whenever the clinicians are struggling with the literature on the human side, I point them towards the marine micro side, because that literature is so strong. It's such an important cycle for the ocean, for food webs, for global carbon. It's really just amazing that it's happening on this micro scale, I guess, in the human body. The math coming from that literature is at play in our guts with cholera and phages, and there's much more similarity than difference. It's just in the human infectious disease space, especially in the GI space, there's just been less opportunities to study it at scale.

And it's just that cholera is such a scaled organism. Like at our center in Dhaka, we have 1000 to 2000 cholera patients admitted per day. It's very hard to manage clinically, but from a scientific perspective, there's an incredible amount of science be done in a short time. That you can't do with other diseases. You talked about the phage destroying the bacteria, making it hard to detect.

Sarah Crespi

But you also had a lot of concerns about COVID antibiotic use, so it wasn't prescribed to people, but there was a chance that they also had that going on when they came in. So, sadly, you know, we're a polluted world when it comes to antibiotics. And if you ask our average patient in Bangladesh, when they come in, did they take a drug? Maybe half of them will say yes. But if you do mass spec, nearly all of them have drug, and usually it's two or more, and we haven't built that into our experiments historically.

Yeah. And now in this paper, we're pulling in phages which historically were forgotten a bit. We're pulling in truth, on antibiotic exposure with mass specifically. And then, you know, I think of this as almost like the swedish chef, where you put it all in the pot and you see what you get at the end of the day. So you wanted to know how much bacteria they have, how much phage they have, and then if they have taken antibiotics, and then you can sort out and kind of see the fate of their dehydration or their, like, clinical progress based on those variables.

Is that what you were looking at? Yeah, that was the kind of grand hypothesis, which is if you look at two patients that seemingly are identical, why is one in shock without a distal pulse? And why is one having mild dehydration sitting upright, eating a banana and watching tv? What's biologically going on there? So in this experiment, we're asking, are phages a determinant of that?

Paul Voosen

Are antibiotics a determinant of that? And what's the interaction of those? Say you have a patient that has antibiotics and phage, are they even better? Are they the sitting up eating a banana people? Or is it more fine grain than that?

It's always more complicated. Yeah. This is a hypothesis that was on the table about ten years ago when we started these clinical trials, and I thought it would be like a drug detected? Yes. No.

A phage detected? Yes, no. And what was the correlation with severe disease? And after, I don't know. I was like six months to a year of analysis of was it detected or not?

We didn't really find anything. The hypotheses weren't sorting themselves out. And then I read back into some older literature from some of my heroes, and there's some work that was done that said, don't just think about was it detected or not? What is the relationship between predator and prey as almost like a biomarker of a readout. And so we began looking at the data in terms of ratio.

And we had this idea of thinking about effective predation was if you have a lot of predator being the phage, with not a lot of prey being the vibrio cholera, if that ratio is high, effective predation was that the correlate with mild dehydration, and then if it was ineffective, predation being the opposite, were those patients severe? And once we flipped that question into a ratio and a biomarker question, then the analysis kind of jumped off the page within a day. It was pretty exciting. That is, it's very much like an ecological perspective on what's happening. Like thinking about predator and prey ratios.

Sarah Crespi

That's not usually something you think about happening in the gut, right? You think about it out there on. The savannah, be it Darwin's finches, or gazelles and lions on the savannah, or like you said, phytoplankton, the ocean, the math is the same. Yeah. And we think about ten to 100 bacterial cells in our gut compared to our own us cells.

Paul Voosen

But then the phages have ten to 100 on top of the bacterial cells. So that biology isn't super well understood, but it's happening right now, as I chat with you. So you did see this correlation then between your ratio of predator to prey and dehydration state. Once you be able to get that number or that ratio out, you were able to kind of make predictions or better understand people's cases? That's correct.

So that was kind of the first discovery, which was once we looked at things with ratios, we could draw clear lines to disease severity. And even if you don't go beyond that first discovery, it's really important because you can use that discovery to think about confounding in clinical trials, how to think about not just building diagnostics, but also true positive versus false positives, true negatives versus false negatives on the diagnostic side, and also epidemiologically, like the numbers you gave on disease burden, are probably huge underestimation of true cholera burden. And it's just that we can build these things into our either current suite of diagnostics, or we can think about a future where metagenomics can not only identify the pathogen, but they can actually predict the disease severity now and in the future. And then I think we're going to get to a place where you can actually use the profile from the metagenome to say, look, there's probably an antibiotic in this patient that you don't know about correct for that factor, so that your clinical decision in epidemiology is more spot on. I also want to get to, you know, as I mentioned before, this arms race idea that, you know, antibiotics, you're worried about microbes getting more and more resistant to them.

Sarah Crespi

There's also a similar thing that can happen with a phage, where the bacteria can evolve and basically protect itself from this virus. What did you find out about that process in your study? That's super exciting? So I'll just let the listeners know that the whole phage evolutionary piece came after we submitted the paper. Was it from a helpful reviewer?

Paul Voosen

Perhaps it was partly from the reviewer, but also Naima Mahdi, the first author. She's brilliant. And usually you don't want to go beyond what the reviewers ask you to do, but she went beyond, and we debated, like, do we include this in the paper or not? And we just went for it. And for those kind of evolutionary biology nerds out there, there's someone named Van Valen, not Van Halen.

And Van Valen has this old theory from, like, 1973, around something called the Red Queen hypothesis, which is both the predator and prey have to run just to stay in the same place. And while the first part of the story was if you have effective predation, in which you put the squeeze on the pathogen by the phages and you have that ineffective predation, you have mild disease. Does the pathogen have increased genetic diversity? That was where we started. And then Naima kind of flipped that around and said, will it happen if the predation is ineffective?

Will the squeeze be on the phage particles? And you'll have increased genetic diversity. That's the part that came, actually, after we submitted the paper and she showed it. And so you really close that loop in the red queen hypothesis in a way that hasn't been shown very often in human medicine. Wow.

One thing that you kind of started with was that this is real. In the global task force for cholera control, which is at the whole, that team there is dealing with nearly 30 countries that are battling large scale cholera outbreaks, and a whole long list of people have studied cholera for all these years. And you would think that in this day and age, we would be doing a better job. But you have this gaps in the science, gaps in the clinical approach, and then challenges with economics and leadership and war that make this problem very real and present. There's also, like, a clinical piece, which is, does anyone in the US or developed world care about cholera?

Sarah Crespi

Yeah, we should. Yeah. So, like, you know, my paycheck is from the US taxpayers. Why should the US taxpayer care about cholera in Haiti or many other places? And I would say we have a humanitarian obligation there.

Paul Voosen

But you could also make a case that if you have a urinary tract infection and you're on University of Florida campus in our hospital, everything that we just chatted about is probably at play in your bladder when you're taking a drug, when you have E. Coli in your bladder, and when phages may or not be there. And if a patient says, oh, where are you going? To look at those drug concentrations and the phage dynamics? I'll say, well, that's not even on the table in terms of how we train clinicians or how we approach things clinically, but it should be now in the future.

Sarah Crespi

So there might be all kinds of common infections where the bacteria we are testing for it, but it turns out there are also phage that are targeting those bacteria, battling it out inside of our bodies, and we are not trying to detect that. And as you mentioned, if there's a phage involved, there could be, this could be a confounder in all kinds of infectious disease trials, not just for cholera, but for other kinds of infections. Trials are really expensive to run. Yeah. Wouldn't it be a bummer if you get one of those kind of 0.09 p value studies and you're like, oh, it sort of worked.

Paul Voosen

But then if you assayed for these phages, and then you went on to look for these ratios and you did some math spec, and suddenly you found a much more meaningful finding. That's important. And as we try to come with better suites of antibiotic regimens, we need to build this into our standard of practice. Thank you so much, Eric. Thank you for your time.

Sarah Crespi

Eric Nelson is an associate professor in the departments of pediatrics and Environmental and global health, and in the Emerging Pathogens Institute at University of Florida, you can find a link to the paper we discussed@science.org. Podcast and that concludes this edition of the Science Podcast. If you have any comments or suggestions, write to us at sciencepodcast aaas.org to find us on podcasting apps. Search for Science magazine, or you can listen on our website, science.org podcast. This show was edited by me, Sarah Crespi, and Kevin McLean, with production help from Megan Tuck at Prodigy.

Jeffrey Cook composed the music on behalf of science and its publisher, AAA's. Thanks for joining us.