These hungry immune cells tidy sleeping flies' brains

0:23Welcome back to the Nature Podcast. This week, the immune cells that clean fly brains during sleep, and the Europeans that didn't become farmers. I'm Nick Patrick Howe. And I'm Benjamin Thompson.

0:46Although researchers don't fully understand why, sleep is important. It's a behaviour that's found across the animal kingdom. Humans, hydra, ostriches, octopuses, we all enjoy 40 winks. And while the exact mechanisms can vary, generally, but not always, sleep has some shared characteristics. It's reversible, so it's not death. While you're asleep, it takes more to get your attention, that's why I have two alarm clocks, and the less you have of it, the more you need it. Sleep is a time when the body performs a lot of important housekeeping tasks, things like storing memories and cleaning out waste that may have accumulated in the brain during waking hours.

1:34Understandably, much sleep study focuses on the brain, but sleep, and in particular the lack of sleep, can affect the whole body, things like the workings of the immune system, for example. But there is some evidence that things can work in the other direction too And that's what our first story is about today A team have a paper out in Nature this week Detailing how a type of immune cell found in fruit flies can affect the insect's sleep One of the authors of the paper is Amita Segal From the University of Pennsylvania and the Howard Hughes Medical Institute in the US I called her up and she laid out the question the group were trying to answer with their research.

2:16So we were interested in determining whether cells of the immune system are relevant for sleep. They were all these molecules and also they were more relevant under pathological conditions. So the question was with daily sleep, is there an immune contribution? And in particular, are the cells important? And why was this a question then? Because the two things don't necessarily seem obvious that they go together. The answer is, I wish I could tell you that it was this great insight that led us to this. But it so happened that the postdoc, who is first author of the paper, came to the lab having trained previously on cells of the drosophila immune system.

2:59So he was interested in linking what he had done as a student with what we were doing here. So kind of a happy accident almost then that you've come to look at this. That's glorious. And so in this work, then you're looking at these cells called hemocytes, which are part of the fruit fly, the Drosophila immune system. Why them and what do they do? So the reason these cells is because they are the major cell type in circulation in the fly. And these cells are like macrophages. So what they do is they engulf, they can take up lipids also, but they also can take up microbes. And that's kind how they contribute to defense mechanisms.

3:38So this group of cells then, which are analogous to the circulating macrophages in human bodies, you show in your paper that they seem to do something peculiar when a fruit fly is asleep. They're circulating generally, but they seem to amass in one particular place. Right. So normally these cells have been studied in the context of development. So flies go through these larval stages, so they've been studied in larvae, or in the adult, they've been studied in the periphery, in the body, right? Not so much in the head. So what we did, which is what Thumbsick, my postdoc, did was to see whether he could visualize them in the head cavity.

4:13And what he found was that in that head cavity, there were more at times of sleep. And in your paper, I think you show that these immune cells aren't just rushing to the brain and completely found throughout the brain. They're really found in a particular area? Because in humans, at least, the brain is very good at keeping the outside out on the inside in, I suppose, the blood-brain barrier. And a similar thing was shown here. Right. So there is a blood-brain barrier in flies. And so they don't seem to be infiltrating the brain. They're sort of on the surface, but in particular on the dorsal surface.

4:45So it actually happens to be the part of the brain where there are a lot of neurosecretory cells. So if you're familiar with the mammalian anatomy, you know, the hypothalamus that has like these huge cells that secrete peptides and are involved in like feeding and sleep. So fly anatomy is very different from mammalian, but this would be roughly that analogous part of the fly bird. And so what you're saying is that during times of sleep, when the fruit fly is asleep, these immune cells move, they circulate to just on the outside of the brain. And was this a surprise when you saw this happen? Was this something you were expecting?

5:22No, not at all. And it was like, oh, wow, you know, why is this happening? And let's get into why you think this is happening. What do your results suggest these immune cells are doing? Yeah. So we asked, you know, do they have anything to do with sleep? And so what we wanted to do then was disrupt their major function and see whether that affects sleep. And we know that their major function is phagocytosis. They take up microbes so they take up lipids. They had been shown to take up lipids from other organs in the fly. And so we basically knocked out or knocked down the major cell surface proteins that would be involved in this particular process.

6:07And we found one that had a very significant effect on sleep. And this protein is encoded by a gene called ETA. Yeah. So what we think happens is that when the animal falls asleep, then these cells that have the ether on the cell surface, they track to the brain. And in particular, they contact the blood brain barrier. And then what they do is they take up lipids from the brain. Where are these lipids coming from then? What are they? So these lipids are getting into the hemocytes from what we call cortex glia, that accumulate lipids during sleep. How they're getting into the cortex glia is from the neurons.

6:48And the neurons are passing on these lipids to cortex glia to protect themselves from oxidative damage. So essentially then it's a system for taking out the trash, if I may. Exactly. So within the brain, then the neurons create these lipids as byproducts of their activity. These are then being passed onto the glial cells and then being passed onto these immune cells, which are then eating them. Presumably, this is an important thing to do. This is an important thing to do, because if you don't, and if you leave all the lipids in there, like if you don't have the relevant protein on the hemocytes to take up these lipids, then they build up in the brain, and you build up more oxidative damage in the brain, and the flies, you know, have impaired memory, and they also have reduced sleep, and they have reduced lifespan.

7:36So you show they have this role. If they're impaired, Ed, what happens to the process of sleep itself? So I'm telling you that these hemocytes are serving a function of sleep, right? So when that function is not being served, typically we would expect sleep to increase, right? Because now the function of sleep is not efficiently being served. So you need more sleep to accomplish it. And yet we see a decrease in sleep. And why is that? And we think, and this is kind of a hand-wavy answer, is that it's because of the buildup of damage that they just cannot maintain a normal cycle. And what do you think this result shows?

8:15Because you're looking in fruit flies, which are a model organism, of course, and you've discovered this mechanism that seems to be important for an important part of sleep, which is tidying up the brain when an animal is asleep. What do you think this might mean more broadly? First of all, I think that it supports the idea that lipid metabolism can be a way of clearing oxidative damage. Secondly, I think it emphasizes how important the transport of lipids is for animal physiology, and in particular, that a buildup of lipids, I would venture to say in any tissue is going to be bad. This one is specific here, but it is also possible that these macrophages, which we have studied with respect to their role in the brain have similar functions with other tissues and maybe that does happen during sleep it has to be said though i guess i mean there was a bit of a leap between a fruit fly and a human i think it seems fiendishly complicated and even in your paper you say it sometimes it's not clear exactly how this works absolutely what questions are key for you to answer next you think i think one of the things that we're interested in is what are these lipids.

9:26The other actually does relate to neurodegeneration. We are looking at actually now fly models for like neurodegeneration for Alzheimer's to ask whether sleep loss is contributing to pathology in that case via buildup of lipids. And do you expect this pathway to be existing in other places? I mean, what do you think? What does your research show at the moment? At this moment, we can only speculate. I mean, as you said, it's a leap to be saying, well, yes, it does, and it could be relevant to your degeneration. On the other hand, if I'm thinking broadly, then I would venture to say that it may well be conserved in those scenarios.

10:05Amita Segal there. To read her paper, look out for a link in the show notes. Coming up, ancient DNA evidence tells a more nuanced story about the history of people in Europe. Right now, though, it's time for the Research Highlights with Dan Fox.

10:24An evolutionary Catch-22 has trapped a type of beetle in a symbiotic relationship with a hostile species of ant. Obligate symbiotic relationships, in which one organism can no longer survive without another, are common in nature. But it's unclear how such organisms evolve and then maintain these relationships. Symbiosis is especially fraught for Septobius lativentris, a beetle that lives among velvety tree ants. These ants form giant colonies and tend to kill intruders. The beetle evades detection by harvesting chemicals called cuticular hydrocarbons found on the ants' exoskeletons. These molecules camouflage the beetle, making it smell like an ant and also prevents them from drying out and dying, as adult beetles cannot produce their own.

11:15Researchers studying the relationship think the beetle's dependence on acquiring cuticular hydrocarbons from the ants locks them in a lethal dependence. If adult beetles regained the ability to produce their own chemicals, the ants would detect and kill them, and if they stopped grooming the ants, the beetles would undergo lethal desiccation. You don't need to evolve a symbiotic relationship with killer ants to find that research. It's in cell.

11:46Oil and gas-producing regions of the continental United States give off up to five times more methane than is reported to government regulators, according to new research. That finding comes from measurements made over a five-month period in 2023, using an aeroplane equipped with a methane-sniffing sensor. In total, the scientists measured methane emissions equivalent to a release rate of 9 million tonnes a year. Some of that was emitted by sources such as landfill sites and agriculture, but 90 % of it came from oil and gas production, at rates much higher than those officially reported to the US Environmental Protection Agency.

12:23The work adds to a growing understanding of how oil and gas fields can be the sources of massive leaks of methane, which is a potent greenhouse gas. Sniff out that research in atmospheric chemistry and physics.

12:43Let me tell you an oversimplified story of some of the ancient people of Europe. After the end of the last ice age, a group known as the Western Hunter Gatherers swept across Europe. As the name suggests, this group subsisted by hunting and gathering. And they were pretty successful, largely replacing the previous populations who had lived in Europe. But then came another group. Around 9 ,000 years ago, the Anatolian farmers started to spread from the Middle East into Europe. They, unsurprisingly, brought with them farming techniques.

13:29And over the next few thousand years, this group largely replaced the Western hunter-gatherers. There's, of course, a lot more nuance here. But according to genetic and archaeological evidence, this is largely what is thought to have happened. But now a new paper in Nature looks at a region where this didn't happen, in what is now the area in and around the Low Countries, the Netherlands, Belgium and Luxembourg. And the people here actually later became a key part of the spread of culture that was hugely influential across Europe, and appear to have totally replaced the existing population of Britain in ways that remain a mystery.

14:25We thought when we came into the study that they would just be like everybody else. But it turns out that in many ways they're the most interesting people in Western Europe at this time. This is David Reich, a geneticist and one of the authors of the new study. The idea that this group would be so interesting was a surprise to David, as when he and his team started looking into this region, they thought it would be much the same as the neighbouring regions that have been studied. And what happens in all of these places is that when Anatolian farmer ancestry gets to these places, it becomes the overwhelmingly dominant ancestry.

14:58In that part of Europe, maybe 80 or 90 % of the ancestry is from those sources. In Britain, maybe 80 to 90%, for example. But when you look at the people from the Low Countries, it's extremely different from that. Anatolian farmer ancestry starts trickling in, but it really stays about 50 % only, with 50 % of the ancestry being hunter-gatherer origin, for several thousand years later than everywhere else. So that was a big shock. By looking at DNA from the remains of 112 people from the region, dated to have lived between 10 ,000 and 3 ,700 years ago, they showed that ancestry from Western hunter-gatherers persisted in the region for around 3 ,000 years longer than most of the rest of Europe.

15:46Now, it has to be said that for archaeologists, this wasn't hugely surprising. It had been known for some time that this region was quite different from the surrounding areas. So the DNA seems to largely back that up. But when it comes to why this group of people seem so resistant to influx on the farmers, the team have got an idea. I think that's for a large part related to the specific type of landscape that these people lived in. This is Avelina Altena, an archaeologist and another author of the new paper in Nature. So these first farmers, we see all over Europe that they really settled on areas with a specific type of soil that is super fertile and really really suitable for the type of agriculture that they performed and the soggy wetlands to call them like that like the coastal areas especially in the netherlands but also the riverine areas in the central netherlands they simply weren't that suitable for the type of agriculture that these first farmers performed and while these soggy areas weren't great for farming it seems that for hunting they were pretty great, so Avelina and David think there was no real need for people in the region to give up hunting, especially when the farming techniques that were being brought in didn't really work for the places they lived.

17:03That's not to say that this group didn't do some farming, but to nowhere near the same extent as other parts of Europe. And while their lives may have been different, there is evidence of mixing going on between the incoming Anatolian farmers and these Dutch hunter-gatherer holdouts. Over time, there was a small influx of farmer DNA into these communities. One surprise for Evelina, though, was who was doing the mixing. The little introduction of this farmer ancestry into these more or less still hunter-gathering communities was mostly through women. There's no archaeological or written evidence to explain exactly what the nature of this exchange was.

17:47But it seems that women from the farming communities did move into these mostly hunter-gatherer groups, taking their genes with them. There may have also been a bit of transfer technology too, as there have been ceramics discovered that resembled those of the farmers in the places where the more hunter-gatherer groups lived. So we do see the adoption of some elements of the farming lifestyle. I think they took what was useful for them. So just not the whole package, but parts of them that were applicable in their specific type of landscape and that fitted their specific type of lifestyle. There was also some male-dominated transfer too.

18:27Another group that took Europe by storm was the corded ware culture, so named due to the cord-like patterns on the pots they produced. This group brought a lot of stepherder DNA into the continent. but for these Dutch holdouts they didn't seem to gain as much of that ancestry as a lot of the rest of Europe even though they took on some of the cultural aspects. But in this case the DNA they did get seemed to come largely from males. Again we can only speculate as to the nature of this exchange. Over the millennia the hunter-gatherer group in and around the low countries took on more and more pharma and corded ware DNA.

19:10This appeared to be a rather gradual process. And then there was a bit more of a dramatic shift. That completely changes after about 4 ,500 years ago with the arrival and advent of a new cultural phenomenon called the Bell Beaker Complex or the Bell Beaker Culture, which is associated with a burial tradition with these bell-shaped pots and archery equipment. Sometimes it's interpreted as a religion. And it originates first a couple hundred years before in Iberia, amongst people who are basically farmers. Despite originating in southwestern Europe, this culture spreads out, meeting the people already living in the Low Countries.

19:51There's a fusion to form a new population that adopts this Iberian tradition or religion. And this new population, which is maybe 85 % corded ware and maybe 15 % local aftergatherer slash farmer ancestry, that then explodes dramatically all over. This new population spreads out across Europe, known as the Bell Beaker expansion. This had a particularly significant impact on the land where I live, which up until then was mostly descendants of the Anatolian farmers, Great Britain. In Britain and Ireland, And it is completely transformative. So, for example, in Great Britain, 90 % plus of the population, maybe even 100%, is replaced by migrants from the continent with a very sharp break in ancestry.

20:37The last big stones at Stonehenge that were built were built by the descendants of the farmers. But within 100 years, they were essentially gone locally and replaced by the stream of people. And what we learn about from this new study is that they were coming from the Low Countries. How this group of people from the Low Countries replaced people in Britain so totally is unclear. It's possible that it was a violent takeover, but it's also possible that the people in Britain suffered from disease epidemics, allowing this new group to move in. We don't see clear indications for one factor that could explain this situation.

21:13So it's likely that it's a combination of factors that genetically this new population seems to have taken over. And one other complicating factor here is also that this is a period where cremation also took place a lot. And unfortunately, these remains are inaccessible for ancient DNA because the DNA just completely disappears there. Or it gets damaged to such an extent that we cannot analyse it anymore. There are many other mysteries remaining about these people from the Low Countries. The team found three individuals in this region who had mostly Anatolian farmer DNA. So there's a question of how they related to this group.

21:54But overall, this study seems to back up the idea that archaeologists have proposed. But this region was somewhat unusual. So other researchers I spoke to, archaeologists who have expertise in this region, said this is kind of the model that we were working with to begin with. This is Ewan Calloway, one of my colleagues here at Nature, who writes about ancient DNA and has been reporting on this new story. The archaeologist he spoke to told him that they expected the people here to be different from other parts of Europe, as the land was so unsuitable to the types of farming that made the Anatolian farmers so successful.

22:31It also supports the idea that there was some mixing between the Coded Ware complex with their steppe ancestry and the farmers. And so this kind of, you know, backs up what we've been seeing, which is kind of an adoption of some farming practices, an adoption of some pottery styles associated with the spread of this steppe ancestry. But while this part of the story may not have been a surprise to archaeologists, the idea that the bell beakers that came to make up so much of the ancestry of Britain came from this region wasn't totally clear. The people I spoke with said that this has made a convincing case that this is the source of Beaker ancestry.

23:09They made it to Britain and elsewhere. Again though, exactly how they came to replace the previous people of Britain remains a mystery. So what does this strange story of the Dutch hunter-gatherer holdouts tell us? Well, it, along with previous archaeological evidence, adds a bit of nuance to the human history of Europe. It's not a simple story of farmers taking over. And it shows how looking at specific regions could uncover surprises. And perhaps the assumptions are just that. I think that the thing that people should realise is that one's assumptions about the past are almost always wrong. And the assumption that this part of the world follows the trajectory of its neighbours is wrong.

23:55So I think that the more general thing one should learn about looking at ancient DNA data is such data are almost always surprising. And it's always important to look at data from a place you haven't studied before rather than just assuming it looks like all its neighbors.

24:21That was David Reich from Harvard University in the US. You also heard from Avelina Altena from Leiden University Medical Centre in the Netherlands and Nature's Ewan Calloway. For more on that story, check out the show notes for some links. And that's it for this week's show. Don't forget to look out for us on Friday when we'll be back with another edition of The Briefing Podcast. In the meantime, you can reach out to us on social media. We're at Nature Podcast. Or you can send an email to podcast at nature.com. I'm Nick Pertcher-Ciao. And I'm Benjamin Thompson. Thanks for listening.