Benjamin Thompson
Welcome back to the Nature Podcast, this week: why leukaemia risk is so much higher in children with Down’s syndrome.…
Emily Bates
...and the latest from the Nature Briefing… I’m Emily Bates.
Benjamin Thompson
And I’m Benjamin Thompson.
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Down’s syndrome is a genetic condition often associated with a number of cognitive and physical health impacts. It’s caused by having an extra copy of chromosome 21 — meaning that three copies are present in each cell, known as trisomy. This week Nature has a paper out that’s been looking to understand something that’s puzzled researchers — namely why children born with Down’s syndrome often have issues relating to their blood. For instance, many newborns have elevated levels of red blood cells — which often drop back to regular levels pretty quickly — but alongside this there can be other issues too.
Ana Cvejic
Maybe something that is less well known, but something that that we were particularly interested in is that these children, they have 150-fold higher chance of developing leukaemia compared to the children that do not have trisomy of chromosome 21.
Benjamin Thompson
This is Ana Cvejic from the University of Copenhagen in Denmark, one of the authors of the paper. The risk of developing a type of leukaemia is hugely elevated for these children in the first five years of life and Ana and her colleagues have been working to figure out why this might be, building on the work of other teams.
Ana Cvejic
What we actually know now for a decades is that all of these events that we are seeing early in childhood in children with Down’s syndrome are actually having their beginnings during fetal development, which will later on in a certain sequence of events lead to development of the leukaemia.
Benjamin Thompson
Previous research established that cells at the centre of this sequence are haematopoietic stem cells — which have the ability to divide and develop into the various types of blood cells, and established that certain genetic mutations played a key role. But Ana wanted to dig deeper into what’s going on in cells that have an extra copy of chromosome 21, and how this might lead to leukaemia and other blood-related issues. First, she and her colleagues took a snapshot of all the individual cells in fetal liver samples. Much of their work concentrated on the liver, as it’s one of the main places in a developing fetus where blood cells are produced. This cellular census matched what others had found.
Ana Cvejic
So what we were seeing is what other people also reported before, and that is that we are seeing increase in the number of stem cells, and we were seeing increase in the cells that will make red blood cells and platelets, and there is a decrease or impairment in immune cells, like B cells. And they were using certain set of technologies to observe this, we are now using a different technology. So the first question is, ‘can we actually see something that was described by others using other technologies?’ So if we can see what other people saw, that's kind of reassuring, because it means that our analysis is kind of good enough to capture these changes, and it's a good starting point to then dig deeper into the mechanisms.
Benjamin Thompson
Levels of haematopoietic stem cells are known to increase in the liver of those with Down’s syndrome, but while these stem cells had the potential to become a number of different blood cell types, they were much more likely to follow the path that led to them becoming either red blood cells — also known as erythrocytes — or platelet-forming cells. To understand why, Ana and the team looked at the genomes of these cells to see what effect having an extra copy of chromosome 21 could be having. They showed that it was leading to changes in the way DNA is packaged. Now, DNA isn’t just floating around inside a cell's nucleus as a simple double helix. Essentially, it’s found wound around proteins — like string wound around a set of beads — which compacts and packages it into a structure called chromatin. This packing plays a key role in gene expression — different sections of chromatin on different chromosomes are unwound at different times, allowing specific genes on the DNA to be turned on and off when required. And it turns out the presence of the extra chromosome was changing which DNA was available.
Ana Cvejic
So basically, for cell to be a stem cell, it has to have certain properties, and one of these properties is to have the ability to make many different cell types. But it can achieve that by having many different regions open, kind of having options open, like which direction it’s going to go, whereas what we're seeing is a really kind of big restructuring of the chromatin accessibility in the stem cells that they're narrowing down their options so they're actually kind of preferentially opening regions which are going to regulate the gene expression of the erythroid lineage genes, and that is then causing higher expression later on of these erythroid genes, and pushes these cells towards erythroid lineage.
Benjamin Thompson
These ‘regions’ are where things called ‘transcription factors’ can bind. You can think of transcription factors like on/off switches for genes. Changes to the chromatin opened up areas for them to attach, turning on genes related to the proliferation and differentiation of stem cells, which could help explain why high counts of erythrocytes — of red blood cells — are seen in newborns with Down’s syndrome. But what of the increased risk of leukaemia? Well, by making use of previously collected data the team identified that changing the chromatin structure altered the chances of where mutations to the DNA could occur.
Ana Cvejic
We see that these mutations are preferentially happening in these areas in which these transcription factors are going to bind. So you can imagine, if that is mutated, that can cause like transcription factor not to bind or to bind differently, and then can cause changes in gene expression. So at the stage when we are looking, none of these are causative of any phenotypes that we are seeing. But in the future, if some detrimental mutation happens in a right place, then it will cause pre leukaemia and leukaemia.
Benjamin Thompson
The team didn’t see this process happening, but their snapshot of the state of fetal cells gave a sense of what could happen further down the road if damaging mutations occurred, ultimately leading to genes being activated incorrectly. But what could be driving these mutations? It turns out that altering the chromatin structure is doing something else as well.
Ana Cvejic
So one of the things that also became very clear that is happening in stem cells in the fetal liver was that these cells kind of had changes in a gene expression, which suggested that there is an oxidative stress happening in these cells, and this comes from dysfunction of mitochondria. So these are the what they call the powerhouses inside of the cell, which provide the energy for cell to function.
Benjamin Thompson
Oxidative stress is an imbalanced state where a cell has too many molecules called Reactive Oxygen Species. These have a dual role — they can act as a signalling molecule, but they can also act as molecular wrecking balls, smashing into structures like DNA and causing damage. These Reactive Oxygen Species are thought to play a key role in introducing mutations into the genome of these cells with an extra copy of chromosome 21. And these different pieces, the oxygen species, Ana’s findings about the opening up of certain areas of the genome, and that some areas are more prone to mutation could all come together to help explain why leukaemia risk is so elevated in children with Down’s syndrome.
Sébastien Malinge
The big strength of this paper is like providing the data on top of explaining many of the phenotypes for many research to come and try to dissect even further.
Benjamin Thompson
This is Sébastien Malinge, a molecular biologist at the Kids Research Institute Australia who studies how leukaemia develops in children. He’s written a News and Views article about the new research. He was impressed by the work and the insights it provides into how blood disorders could begin to come about within fetal livers.
Sébastien Malinge
It was known that those disorders appeared extremely early, and it was known that it was due to the Trisomy 21 but what was not known is how it works, right? And I think the strength of this work, the strong power of this work, is to give clues about how those things happen. It's been done very deeply, right? They use single cell sequencing to interrogate every single cell to know where those traits are coming from.
Benjamin Thompson
Sébastian says this research provides a strong foundation for future work to further unpick what causes the events to happen, but there’s still much to learn — for instance, he’d like to get a sense of what’s going on with the genome at an even earlier stage.
Sébastien Malinge
Personally, I would like to know what's happened before. So we see this snapshot of the open chromatin, but how does that happen? Really? We don't know. If it's like a big burst happening at one specific time, or it's a slow process during the several weeks. We don't know. I think it's very interesting question that it's going to be very hard to answer.
Benjamin Thompson
There are lots of other things to understand too. In this work Ana identified a sub-population of stem cells in the liver that seems to cycle a lot faster and have an even more pronounced bias towards ultimately becoming red blood cells. And then there is the fact that what was seen in liver stem cells was not seen in bone marrow cells — another place that blood cells are made. And other tissues can have different gene expression patterns. So what is it about the presence of the extra copy of chromosome 21 that’s driving all this? Ana’s got some ideas.
Ana Cvejic
Clearly, because there is additional chromosome 21 there could be upregulation of the genes which are encoded by chromosome 21 and this is automatically going to change kind of regulatory networks. But you can also think that having additional chromosome for a cell is a burden, because, you know, a lot of things will change in a metabolism of a cell in terms of how much proteins there are and so on. And then you can also think physically, like how all of these chromosomes are packed in the nucleus. So you can think that having additional one can kind of cause some pressure, like on a cell, space-wise.
Benjamin Thompson
Finding out which, or which combination, of these is the driver is going to be difficult. But it’s important to remember that people are at the centre of this. Children with Down Syndrome’s are at a vastly higher risk of leukaemia and both Ana and Sébastian hope this research will be a step in helping to understand why this is. Sebastian says that while leukaemia treatments are available, ultimately not needing them would be a huge benefit to these children.
Sébastien Malinge
If we can decrease the higher risk of these children to have leukaemia, that would actually be a long-term goal, right. And that's only very important step this paper to start providing some key features to find those indicators. So there’s treatment exists as we save life more than 50 years ago. But like the price is a toxicity and the long-term secondary effect, right of all those toxic treatment so whatever we can find to actually avoid to use life-threatening treatments is a key in the future of research for leukaemia, specifically.
Benjamin Thompson
That was Sébastian Melinger. You also heard from Ana Cvejic. To read Sébastian’s News and Views article and Ana’s paper, look out for links in the show notes.
Emily Bates
Coming up how tiny crustaceans can smell their way home. Right now, it’s time for the Research Highlights with Dan Fox.
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Dan Fox
Researchers have found a straightforward way to reduce beer consumption amongst English pub-goers – take pints off the menu. At 568 millilitres, the imperial pint is among the largest serving sizes of beer in the world. It's also the most popular serving size for beer in the United Kingdom – so much so that ‘going for a pint’ has become shorthand for grabbing a drink. But alcohol overuse is a public-health issue, spurring a search for ways to reduce how much people drink. Previous work had suggested that people drink less wine when serving-sizes shrink. To check if this held true for beer, a team of researchers tracked alcohol consumption in 13 establishments that had replaced imperial pint glasses with clearly marked two-thirds versions for four weeks. They found that during those weeks, patrons drank, on average, almost 10% less beer per day. And while wine sales rose, it was not enough to offset the drop in beer sales. The study suggests that shrinking serving sizes can reduce alcohol consumption. Drink-in the full measure of that research, in PLoS Medicine.
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In the tropical forests of Costa Rica, a small lizard has worked out a novel way to avoid predators: scuba diving. Semi-aquatic Anolis lizards, like the water anole can stay submerged for at least 20 minutes using an air bubble on their snouts that allows them to breathe underwater. Now, a researcher has tested whether these bubbles actually help them stay underwater for longer. By applying a substance to the lizards’ skin that prevents bubble formation, they were able to see that without air bubbles, the lizards couldn't stay underwater as long as usual: they surfaced about 30% around 67 seconds sooner than lizards that could form bubbles. Next, the author plans to investigate whether the lizards’ bubbles act as a physical gill – similar to those used by certain aquatic insects to extract oxygen from the surrounding water. Read their research in full, in Biology Letters.
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Benjamin Thompson
Finally on the show, it’s time for the Briefing Chat, where we discuss a couple of articles that have been highlighted in the Nature Briefing. Emily why don’t you go first this week, what have you got?
Emily Bates
So I was reading a story in Science. It's all about these tiny crustaceans called mysids that use their sense of smell to find their way back to the caves that they live in. So every night, millions of mysids migrate into the open sea to feed. They leave at dusk, and they return to their deep underwater caves before daylight to avoid predators. And it was known from previous research that they use light to navigate on their way out, but it wasn't known how they found their way back.
Benjamin Thompson
Right. And the ocean's a big place, especially if you’re what a tiny crustacean.
Emily Bates
One millimetres these, these little–
Benjamin Thompson
–really?–
Emily Bates
± mysids, yeah.
Benjamin Thompson
So how did researchers go about figuring out that they were following their nose, so to speak.
Emily Bates
So they took some of these mysids from two different underwater caves, and they placed single animals in these Y-shaped containers. And sometimes one arm of the Y led to sea water taken from the mysids home cave, the other to seawater collected from the other cave. Other times, neither arm led to water from the home cave. All kind of different configurations of that. But overall, the mysids sought out and preferred to spend time in water taken from their home cave. And then they also, in the second part of this study really, the researchers showed that water from each cave had its own distinct chemical signature or smell, which is what they think is guiding the mysids.
Benjamin Thompson
Right. There must be something in there, a chemical X factor.
Emily Bates
So yeah, we know salmon use chemical cues to find their way home in their migration, but now we're seeing it in these really tiny little crustaceans, which I just think is very, very interesting.
Benjamin Thompson
Presumably, this chemical, whatever it is, is coming from the caves into the open water. Any idea what it is?
Emily Bates
So it’s not clear exactly what was giving each cave the sort of unique smell that was allowing these mysids to find their way. But the researchers hypothesized that it could be compounds released by sponges that live in the caves. And so the different amount of different kinds of sponges were giving each cave this very unique smell.
Benjamin Thompson
I mean, we say ‘smell’ here, I think it's easy to sort of anthropomorphize or to, you know, have a human-centric look at stuff, but is this actually a kind of smell as we know it, Emily?
Emily Bates
It is detecting chemical compounds and using that information going into the brain. We don't know how these animals perceive it, but it's as close to smell as we can imagine. One thing to think about around this is with marine pollution and things on the rise, and sponge species there's been a disappearance of some species from these caves, it could change the sort of chemical seascape of these underwater caves. And does that mean that in the future mysids won't be able to find their way home?
Benjamin Thompson
Right. Which suppose could have knock-on effects to the complex food web that exists under the water.
Emily Bates
Absolutely.
Benjamin Thompson
Right. Well, let’s move on to my story this week, and it couldn't be more different. Now it’s a– it’s a perennial favourite here on the Nature Podcast that we talk about ways to deflect asteroids that might crash into Earth and everything that goes alongside and this is a another one of those. And I read about it in Nature. It's based on a Nature Physics paper, but it's looking at things in a slightly different way.
Emily Bates
Interesting. Tell me more.
Benjamin Thompson
Well, so this work centres on whether a nuclear explosion could be used to deflect an asteroid, and that's the sort of thing that's been, you know, thought about in Hollywood and in science for quite a long time, right. But in this case, it's looking at a different part of the explosion: the X-rays.
Emily Bates
Oh, okay, so yes, I was aware of people talking about using a nuclear bomb to maybe, you know, the impact, to push an asteroid off course, but the X-rays?
Benjamin Thompson
Yeah, absolutely. So a lot of experiments have looked at the effects of how the momentum of a nuclear bomb shockwave that results from the expansion of gas could push against an asteroid right–
Emily Bates
–right–
Benjamin Thompson
–and kind of push it off course. But it turns out that nuclear blasts do create a huge amount of X-rays, and the researchers behind this work reckon that this actually might have a bigger effect on the trajectory of an asteroid, and so they set about testing it.
Emily Bates
How do they test it? There are not aren’t enough asteroids out there for us to go and send nuclear bombs up I assuming.
Benjamin Thompson
Yes, admittedly, they did have to mock things up in a lab. And they use this really powerful bit of machinery called the Zed machine, or perhaps the Zee machine, if you're from North America.
Emily Bates
This is already sounding very Hollywood.
Benjamin Thompson
Well, this machine is amazing, right. It uses powerful magnetic fields to produce high temperatures and, of course, powerful X-rays. And one of the researchers involved said that about “80 trillion watts of electricity flowed through the machine in about a 100 billionth of a second”. These are numbers that are difficult to even comprehend, right. And this surge, what it does is it compresses argon gas into a plasma, and this plasma is this weird kind of state of matter, and it’s millions of degrees in temperature, and it emits a bubble of X-rays. So that's how they made the X-rays but the next step, of course, was to make some asteroids.
Emily Bates
What do they make the asteroids out of?
Benjamin Thompson
They make the asteroids out of quartz and silica, okay, so this reflects the different compositions of asteroids in the solar system. Okay, they made two of them about the size of coffee beans, so just little, tiny–
Emily Bates
–little baby asteroids–
Benjamin Thompson
–little baby asteroids. And these asteroids were hung in a vacuum from thin pieces of foil in this machine. And when the X-ray bubble hit the foil, it acted as like a pair of scissors, I suppose, and cut through the foil and the asteroids then put into free fall and the researchers could see what the X-rays did.
Emily Bates
Please tell me, what did they do?
Benjamin Thompson
Right, well, this experiment apparently only lasted 20 millionths of a second.
Emily Bates
These numbers are incredible, okay.
Benjamin Thompson
But both the asteroids were accelerated to around 70 metres per second before being vaporized. But it seems that the cause of the acceleration, the researchers say, was these X-rays, and they were vaporizing the surface of the asteroids, causing, you know, thrust as gas expanded away from the surfaces. So a little bit of a push.
Emily Bates
Would this work on a larger scale? Because that sounds amazing, but does it scale?
Benjamin Thompson
Well, the researchers think that, yes, it could be scaled up to much larger asteroids, maybe four kilometres across, and sort of push them away from a potential collision course. But they do say that potentially, it's most likely to have applications for big asteroids with a short warning time, the very worst ones I suppose, because they think that maybe other approaches, like ramming a spacecraft into an asteroid.
Emily Bates
DART
Benjamin Thompson
–That's right, NASA’s DART. They did manage to move an asteroid back in 2022 and we covered that on the podcast, but that approach might not have enough energy for these kind of short-term emergencies.
Emily Bates
So is this something that we really think is going to be put into action? Are people excited about this idea, or is it– is it Hollywood?
Benjamin Thompson
I mean, there's a lot of questions there. Will it be put into action? That's one of those ones I guess we won't know, and I also hope not. But looking at ways to deflect asteroids is kind of something that researchers are putting more and more time into, and certainly looking at how nuclear deflections might work, but also trying to figure out on Earth how you might test how effective these are, of course. But it seems that other researchers quoted in this News article are positive about the effectiveness of this as a technique, but the team behind it are looking to perform more tests to refine it, and eventually they say, you know, maybe, hypothetically, it could one day be tested in space, much like DART was to see if it could nudge an asteroid.
Emily Bates
I mean, that is amazingly cool. I hope we never have to use it.
Benjamin Thompson
Agreed.
Emily Bates
Well, thank you Ben. And listeners for more on those stories, and for where you can sign up to the Nature Briefing to get more like them, check out the show notes for some links.
Benjamin Thompson
That’s all for this week, as always you can keep in touch with us on X, we’re @NaturePodcast, or you can send an email to podcast@nature.com.
Emily Bates
And if you fancy leaving us a review, you can do so wherever you get your podcasts. I’m Emily Bates.
Benjamin Thompson
And I’m Benjamin Thompson. Thanks for listening.
