Could this one-time ‘epigenetic’ treatment control cholesterol?

Nick Petrić Howe

Welcome back to the Nature Podcast. This week, how the universe's cosmic fog was cleared, an epigenetic way to control cholesterol, and how humans lost their tails. I'm Nick Petrić Howe.

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Astronomers looking at the Universe today can see stars and galaxies from millions of miles away, as light from them floods their telescopes. But in the long history of the Universe this hasn’t always been possible, first because there were no stars, but later because the Universe was filled with a cosmic fog — neutral hydrogen that let through visible light but blocked other wavelengths.

Obviously, that’s no longer the case, but how exactly the Universe emerged from the Cosmic Dark Ages, has been a matter of debate. Around 13 billion years ago, not long after the Big Bang, ionising radiation started to reionise the neutral hydrogen, clearing the fog. But the source of that radiation is unclear.

A new paper in Nature though may clear up this issue, as it has identified a likely culprit of the reionisation. Reporter Lizzie Gibney caught up with one of the paper’s authors, Hakim Atek to chat about the discovery. She started by asking him what the different theories are for reionisation.

Hakim Atek

We had many hypothesis. So one of them was supermassive black holes, that could emit strong radiation that would be able to reanalyse the universe. The problem is that those supermassive black holes are not numerous enough to produce enough radiation. So, the second most plausible explanation of sources would be galaxies that form stars at early epochs and could emit enough radiation to analyse the universe. These were the two main candidates for reionisation.

Lizzie Gibney

And your team has been trying to help shine some light on this debate. What have you been doing? How have you been trying to look back into this period of the universe’s history?

Hakim Atek

So far what we have been doing is getting imaging of this galaxies to try to determine if galaxies are the actual responsible for cosmic reionization. So, our team what we have done here is combined the James Webb Space Telescope with gravitational lenses. So thanks to this combination, we can actually detect and characterise the faintest galaxies ever observed at this epoch of reionisation.

Lizzie Gibney

And what is it that the JWSD telescope can see that others haven't been able to see before?

Hakim Atek

So the James Webb Space Telescope is the most powerful telescope ever built. It's essentially designed to peer into the early universe to uncover the formation of the first galaxies and this famous epoch of reionisation.

Lizzie Gibney

And you're looking at some really faint galaxies that are out there and use a technique called gravitational lensing. Does that–does that boost the light that we're getting from these galaxies?

Hakim Atek

Exactly. So this phenomenon is created by massive structures. So here, we use massive galaxies, its a cluster of massive galaxies that will curve this time, and it will act as a magnifying lens. So we can amplify the light of the distant sources, which would be undetectable even with the JWST without using this gravitational lensing effect.

Lizzie Gibney

So we can finally look at the radiation that's coming off these very faint, very early galaxies. And what did you find?

Hakim Atek

What we found is that despite their size, these tiny faint galaxies are actually very efficient, producing ionising radiation. And the amount of radiation they emit is about four times the value assumed for massive galaxies. And the assumption was that faint galaxies would be like massive galaxies. It turns out, they are not. They are much more efficient at producing ionising radiation than we thought.

Lizzie Gibney

So if we have enough of these faint galaxies, cumulatively we'll be able to produce enough of this ionising radiation to– to dissipate the cosmic fog by themselves.

Hakim Atek

Yeah, so, in this exact study, we also confirmed the number of these faintest galaxies, which is very high. So we combined the number density of these galaxies and their ionising power. So we ended up with enough ionising budget to reionise the universe.

Lizzie Gibney

So it sounds like instead of there being just a few big explosions of radiation clearing out the fog, it's like you've got loads of little candles everywhere and that's doing this ionising job and getting rid of the neutral hydrogen to– to make the universe that we can peer through.

Hakim Atek

Exactly. So it's the little tiny galaxies that by their numbers actually outshine the big galaxies.

Lizzie Gibney

And are you making any assumptions to come to this conclusion?

Hakim Atek

Totally. I think the big assumption here is that the small area we're observing is representative of the large-scale distribution of galaxies in the entire universe. And to do that, we also estimate the uncertainties that come from what we call cosmic variance. So with some simulations, we can extrapolate to the rest of the universe and see how the small variation can affect our results.

Lizzie Gibney

And how does this finding of where the radiation came from that reionise the universe? How does that change our picture of this period and the universe's time? Are we learning anything new about what was going on or what happened afterwards?

Hakim Atek

So in addition to pinpoint the exact sources of reionisation, it also has different implications on galaxy formation. For instance, because low mass galaxies are more evenly distributed as a massive once in the early universe, the exact sources of reionisation also share the global temperature of the gas in the universe, which means the cosmic web of the universe will emerge and form the structures we see today.

Lizzie Gibney

So this reionisation process actually helped shift or form the structures that we still see in the universe.

Hakim Atek

Yes, exactly.

Lizzie Gibney

What's next for you and your team? Is this an area that you're going to keep studying?

Hakim Atek

I think now that we are starting to uncover these ultra-faint galaxies, the question is, how faint we can go and still find galaxies at early times, because there is a theoretical limit of the smallest galaxy that can form stars at cosmic dawn. So we now will have the possibility to directly test our theories. And we have upcoming large programmes to do just that.

Lizzie Gibney

And you mentioned right at the start that some astronomers think that it's actually the matter being drawn into the supermassive black holes isn't it that create radiation? And some people think that it's those that created this ionising radiation? Is this going to be a controversial paper? Or do you think people still stick to their guns and be in the supermassive black hole corner?

Hakim Atek

I think we will have some part of the community that will still advocate for this solution, but if they do, then we will have too much ionising radiation in the early Universe, which will have certain implications also on the growth of structures in the universe, and how the helium reionisation occurs, which is the second most abundant element in the universe. So if you have too much radiation, you will ionise that element too quickly, too early in the universe. And the James Webb Space Telescope is still also telling us about the number of the supermassive black holes in the early Universe. And so far, there are not enough out there to reionise the universe.

Lizzie Gibney

So the evidence is leaning in your favour.

Hakim Atek

We hope so.

Nick Petrić Howe

That was Hakim Atek, from the Astrophysics institute in Paris, in France. For more clarity on this discovery, check out the show notes for a link to the paper. And coming up, we'll be talking about a possible epigenetic way to control cholesterol. Right now, though, it's time for the Research Highlights with Dan Fox.

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Dan Fox

Inscriptions carved on a bronze hand over 2000 years old, might be the earliest written example of the language that eventually became modern Basque. Basque is one of the oldest living languages, and is thought to have descended from a language spoken by the Vascones, an Iron-Age people who inhabited parts of northern Spain before the arrival of the Romans. Researchers analysed inscriptions on a hand-shaped bronze plate that was unearthed from an ancient Vasconic village. They found that one of the inscribed words is similar to a Basque word meaning ‘of good fortune’, and the inscriptions and design suggest that the hand was dedicated to a deity of fortune, and used as a good-luck charm. Archaeologists have long thought that the Vascones lacked a writing system other than that used on coins, but the findings show that these ancestors of modern Basque people already knew and used writing in the first century BC. Read more about that research in Antiquity.

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Dan Fox

Researchers have used lasers to etch a groove into an unexpected surface – soap film. Soap films are thin layers of liquid sandwiched between walls of detergent molecules, or micelles. When a film is stretched or perturbed, any excess micelles in the liquid layer rush to reinforce the walls of the film, quickly restoring is smooth surface. But now researchers have found that if they increase the moving soap film’s detergent concentration beyond the critical point, they could carve long-lasting grooves into his surface using a laser. That's because the high quantities of micelles reduced the film's elasticity, preventing its surface from recovering. The laser pulses created a series of pits in the film; which elongated as the film flowed, creating etchings that resembled dashed lines each less than a millimetre long. You can read that research in full in Physical Review Fluids.

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Nick Petrić Howe

High cholesterol affects millions of people worldwide, increasing their risk of heart disease. To reduce cholesterol many people take statins, but these drugs have to be taken every single day which can be a burden.

But maybe that won’t always be the case. A new paper in Nature shows a step towards making a single treatment which could reduce cholesterol forever, by tweaking epigenetics.

Epigenetics, in general terms, refers to the regulation of gene expression but does not change the DNA sequence itself. Instead epigenetic changes are controlled by things like methyl groups being added to DNA and can increase or decrease the expression of genes. The researchers hope to take advantage of this using a pharmaceutical intervention that contain molecules known as epigenetic effectors which influences genetic expression – in this case – silencing a particular gene that can cause disease.

Now this has been shown to work well in cells in a dish, so in the new paper the team were interested to see if it would work in a full-fledged living organism. Their target was Pcsk9, a gene linked to high cholesterol. I asked one of the authors, Angelo Lombardo and asked him why the team picked this gene.

Angelo Lombardo

Pcsk9 is a modern gene actually it has been used since quite many years, actually. So it’s a well-known gene that needs to be shut off to decrease the level of cholesterol in the blood. So that was a very, let's say, nice and convenient gene to target for this specific group of physical experiments which actually, the biggest question was, is that the genetic technology that we are using sufficient enough now to silence a gene in a living organism for a long period of time.

Nick Petrić Howe

And in this paper, you tried to do this silencing in a mouse model. What was your approach?

Angelo Lombardo

Well the approach is, well, similar to COVID the see so we exploited lipid nanoparticles to encapsulate messenger RNA that qualify for these epigenetic effectors and injected them into mice. So we're not discussing about or talking about vaccination in this specific case, we're talking about transient expression in the liver, which is the organ target, in this specific case, to Pcsk9 transient suppression of these epigenetic effector.

Nick Petrić Howe

As you said, you were trying to see if you could get sort of long-term silencing or less expression of that particular gene, how successful were you in that?

Angelo Lombardo

We were quite successful actually, we can achieve significant level of reduction of Pcsk9. The level of reduction that we achieved, were also linked to the delivery that they use, in this case on the specific lipid nanoparticle that we that we use in our study. We haven't yet reached 100% of repression, we were confident that playing with the delivery with the particles that we use, we can further increase efficiencies.

Nick Petrić Howe

And in the paper, you were able to show that this sort of epigenetic silencing this repression of the genes happened for a whole year for the mice. But you know, I would have thought that as cells divide, maybe they wouldn't have these epigenetic marks on them still. So did you need to like reapply this at any point? Or was this just a case of one and done?

Angelo Lombardo

Well, in this study, not only we follow the mice for one year, but you also perform a surgical procedure which actually activates liver proliferation. You know, liver is a highly regenerative organ when damage and these regeneration implies a significant proliferation of liver petasites And also in that specific experimental context, actually digitally signs in remain stable, indicating really that the epigenetic modification imposed by the technology were, indeed editable. So you hit once it says, memorised that you silence the gene. And these memory remains also to the daughter cells.

Nick Petrić Howe

And so you showed this occurred for a year. But do you suspect that this would last much longer than that?

Angelo Lombardo

That’s the hope, of course, actually, the epigenetic proteins that we use in our editors, they do come from a complex of protein, which is active early during embryogenesis. And these complex of proteins silence endogenous retroelements or retroviruses, which are spread throughout our genome. And the silencing falls early during development in the first same moment of life. Weeks, if not months of life, these epigenetic information are then propagated throughout the entire life of an individual. So I think that's an interesting parallelism, you know, with our technology, and hopefully, also our technology will do the very same, so it wants and then for the entire life of the …..,

Nick Petrić Howe

What do you think that this shows is possible?

Angelo Lombardo

I think that's the first time to our knowledge, at least that someone showed that this transient expression of these proteins is sufficient to impose long lasting no and efficient epigenetic science. So that opens basically, the possibility of using the platform more broadly than before. And then before was proof of principle of the activity of the platform in cell lines. So now that we have indication that this pattern was also in Devo open up so many, many different possibilities.

Nick Petrić Howe

And obviously, in this study, you looked at this gene that's associated with cholesterol, like a lot of people use statins in order to control their cholesterol levels. Could this be an alternative to that?

Angelo Lombardo

Yes, it might well be. So, well the advantage here is that is a single, one and done treatment. So single treatment, instead of taking pills every day, you make a single treatment, and you achieve long-term reduction of Pcsk9 and has no reduction of your blood cholesterol. There are also other editing technology that are similar to this. So can inactivate the gene stably, like for instance, gene editing no, by– by conventional CRISPR cast. An advantage of our technologies is that we are not cleaning the DNA so genome– genome editing acts on the primary DNA sequence by cleaning the double stranded helix of the DNA, this cleavage of the double strand helix may come with some potential no, adverse events, outcomes that probably our technology may have solved. There is another advantage actually, in our technology that there is a potential to revert, eventually, these epigenetic marks that we deposed, so epigenetics can be the cause, and then also eventually reverted sort of antidote eventually.

Nick Petrić Howe

What might we need to do now in order to make this a reality to be used in treatment? This is a mouse study, what do we need to do to sort of scale it up to be used in humans?

Angelo Lombardo

Well first of all, we need to identify effective and safe reagents to silence the human gene. We are still dealing with species specific reagents, the ones that we have used have been designed to recognise the mouse genome. So we need to identify and develop now reagents that can do the very same in the human genome, and then try to scale up the process to move first eventually, in other animal models, bigger animal models, again, to test the efficacy and safety did eventually in human beings.

Nick Petrić Howe

That was Angelo Lombardo, from the San Raffaele Telethon Institute for Gene Therapy, in Italy. For more on that story, check out a link to the paper in the show notes.

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Finally, on the show, where's my tail? This is a question that a researcher asked as a child that prompted some research — now being published in Nature — into the genetic changes that led to humans and other apes losing their tails. Reporter Ewen Callaway has been reporting this story, and he joins me now. Ewan, hi, how's it going?

Ewan Callaway

It’s good, glad to be back on the podcast.

Nick Petrić Howe

It's been a while, we should have you on more often. So as I mentioned in my introduction, this is a bit of research about the genetic things that went on that caused loss of tails in apes and humans. And this has been something that's kind of been on the mind of one of the researchers involved for quite a while, right?

Ewan Callaway

Yeah, yeah. The lead author of this paper Bo Xia, you know, he told me that it's something he'd kind of wondered about as a kid. Why don't I have a tail? It's how I kick off my story. And he kind of maybe forgot about it until he had a coccyx injury. The coccyx is our vestigial tail. And you know that depicted his PhD work, and he decided to try and figure out the genetic basis for why humans and other apes don't have tails.

Nick Petrić Howe

So an injury to what's left of our tail made him wonder about that. And so where did he start? Where did the team start when they were looking at this?

Ewan Callaway

Well, there's two answers to that. If you read the paper, they came up with a long list of genes that were linked to tail loss in different animals, mostly mice. And then, you know, looked for things that distinguished tailless apes from monkeys with tails. What really happened, though, was, there's this really famous gene, it was initially called T. It's called TB XT now that was in the 20s, before we really knew what genes were, linked the tail loss in mice. And, you know, we've known ages that if you delete this gene or muck with it, you can get tail loss. And so what the authors did was they just looked in genetic databases, and found that humans and apes, you know primates that don't have tails have this kind of genetic insertion in a portion of this gene that monkeys, the relatives that do have tails, don't. And so they started doing some experiments to explore this.

Nick Petrić Howe

And so I guess the idea is that if you muck about with this gene in the correct way, with this particular insertion, you'll end up with something happening to the tail. And they were looking at this in mice, right? What did they find?

Ewan Callaway

Yeah, it's quite a lot of mucking about. And it's a really, it's a complicated old mechanism. So hold on to your seats, we'll try and get our way through this. I mean, the insertion is something it's called an ALU, element ALU, these little short things that are peppered across the genomes of primates, only primates, and mostly, they do nothing. In this case, this ALU element 25 million years ago or so landed in a region of the genome in the ancestor of apes, that seems to lead to a shortened version of this T gene, or this T protein that was identified back in the 20s. And so, the researchers theorised that this shortened version alongside a regular length version, so you've got both does something in development that leads to shortened tails. They tried to replicate it in mice, they got some mice with weird tails, some had long tails, some had kink tails. They did some more models, and eventually ended up with mice with a different insertion, but one that tried to mimic what humans and apes had. And lo and behold, you hit the right combination, they didn't have tails. And so that led them to conclude that this insertion in this gene contributed to tail loss in apes, it might have not been the whole story, but it probably played a role.

Nick Petrić Howe

I mean, and you made it sound, like relatively straightforward. But as I understand this was a preprint, a couple of years ago, and it's been quite a long journey for them to get from there to now the Nature paper.

Ewan Callaway

Yeah, yeah back in 2021, which was when I was last on the podcast, but when we were all knee deep in COVID and we had Corona pod, and reporters were covering preprints a lot. This thing bopped on the Bio Archive, about, you know, explaining tail loss and just, you know, caught like wildfire and got a lot of attention. And then three years later, the paper comes out. And so I kind of asked, you know, what, what changed? And it turns out, you know, a lot more mouse work really hammering home the mechanism, the explanation for why this little insertion leads to a shortened protein that leads to loss of tail in mice. So it was a lot of extra mouse work, a lot of CRISPRing happened in those three years.

Nick Petrić Howe

And are researchers kind of convinced that this is a key part of the story then?

Ewan Callaway

I defined convinced in key. I mean, I spoke with one person who named themselves as a reviewer of the paper, and it was somebody who was really asking for this extra mouse work. And he's convinced that this change was important. He doesn't think it was the only one. You know, that's probably not how evolution of big traits works. But I think he was pretty convinced that they made a good case that this played a role.

Nick Petrić Howe

And you mentioned that there may be many other genes that are involved in this, this is probably not the thing that happened. So what's sort of next in our understanding of how we lost our tails?

Ewan Callaway

That hot topic of research. Um, I mean, I'm not sure if the researchers are necessarily following up on this. But one interesting thing is that humans and other apes aren't the only primates that have lost their tails. And they're these creatures called lorises, that have big eyes because they're nocturnal, really funny looking creatures – they don't have tails. Some macaques don't have tails. Mandrels don't have tails. So, you know, as we get more and better genomes of these tailless primates, we could start looking for the genetic basis of those. I think the authors, I think they looked in the case of macaques and didn't find an obvious answer in this T gene so it might lie elsewhere.

Nick Petrić Howe

And what might this mean, then identifying this gene? What could it mean for our sort of understanding of our tailless lives?

Ewan Callaway

Yeah, there's a couple of things to say here. One thing this could link back to is that these mice that had some of these mutations that they spent so many years engineering, had developmental defects that are similar to a condition called spinal bifida in humans. So there's the possibility that by losing our tails — which maybe provided some benefit, and maybe not —we've ended up at risk for this genetic condition. And the other thing I think, you know, worth talking about and I'm not sure if we have an answer is why did we lose our tails? The assumption is, is that you know, everything that happens in evolution is for a reason, the instinct is to say, it must have provided some benefit. There's some, you know, argument that maybe it contributed to walking upright on two limbs. Maybe it helped us to live, you know, down on the ground, not in the trees like primates. But people have pointed out to me that, that bipedality and you know, our terrestrial lifestyle happened a long time, millions of years after we lost our tails. And so one possibility is that it just happened by chance and it stuck. Like so much of evolution, we really don't know. And I'm not sure this is really a noble thing.

Nick Petrić Howe

Oh, I guess the idea that this gene is involved in tail loss stands on its own two feet, but maybe the bipedalism question could be put to one side for now. But I think that's all we've got time for. So thank you so much Ewen for joining me.

Ewan Callaway

You're very welcome. Thanks.

Nick Petrić Howe

And that's also all the time we've got for the show this week. We'll be back next week with more news from the world of science. In the meantime, if you want to keep in touch, you can, we’re on X @naturepodcast, or you can send an email to podcast@nature.com. I've been Nick Petrić Howe. Thanks fo