Welcome 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 Patriciao.
And I'm Benjamin Thompson.
Although 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.
Understandably, 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 Sehgal 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.
So 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.
So 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 haemocytes, 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 of how they contribute to defense mechanisms.
So 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 Bamsik, my postdoc, did was to see whether he could visualize them in the head cavity.
And 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.
So it's 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 brain.
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?
No, 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 or they take up lipids.
They had been shown to, you know, 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.
And 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 eater 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.
And 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.
So you show they have this role.
If they're impaired, 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?
Because 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, Amita, there is 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 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?
The 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 for 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.
Amita Sehgal 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.
We've done Fox.
An 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 ant's 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.
Researchers 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 cells.
Oil 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 airplane 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.
The 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.
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.
And 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.
We 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.
In that part of Europe, maybe 80 or 90 percent of the ancestry is from those sources.
In Britain, maybe 80 to 90 percent, 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 10000 and 3700 years ago, they showed that ancestry from Western Hunter gatherers persisted in the region for around 3000 years, longer than most of the rest of Europe.
Now, 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 from 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 Evelina 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.
That'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.
But 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 resemble those of the farmers in the places where the more hunter-gathering 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.
Another 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 steppe herder 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-wear DNA.
This appeared to be a rather gradual process.
And then there was a bit more of a dramatic shift.
That completely changes after about 4500 years ago, with the arrival an 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.
There'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 people.
After gather 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 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.
The 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.
So 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.
The 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 analyze 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.
But overall this study seems to back up the idea that archaeologists have proposed that this region was somewhat unusual.
So other researchers.
I spoke to archaeologists who have expertise in this region.
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.
It also supports the idea that there was some mixing between the corded 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 and an adoption of some pottery styles associated with the spread of the 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 that 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 realize 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 neighbors is wrong.
So 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.
That 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 Perchichow.
And I'm Benjamin Thompson.
Thanks for listening.
