Squid-inspired pills squirt drugs straight into your gut
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Welcome back to The Nature Podcast. This week, a squid-inspired drug delivery system. And new ways to break down forever chemicals. I'm Benjamin Thompson. And I'm Emily Bates.

Researchers have developed squid-inspired devices that can squirt tiny jets of drugs directly into the lining of the gut or stomach. Now, that may sound like an odd way to get drugs into your body, but a recent study has shown that most people would prefer to swallow a pill rather than have a needle-based injection, the most common way to deliver therapeutics.

But in some cases, much of the pill breaks down before it gets to where it needs to go, limiting its effectiveness. This is the case with insulin, for example. In situations like these, an ingestible device may be a solution to deliver drugs more effectively. But many devices that have so far been designed also use needles, albeit tiny ones. And that is something that still needs careful handling,

at the other end. To overcome issues like this, a team has looked at how squid fire out jets of ink and used this to design a new type of ingestible device that works in the gastrointestinal tract. Reporter Nick Pertrichow spoke to one of the team, Giovanni Traverso, who laid out what the team needed to figure out in order to get their jet idea off the ground. Part of the work that we did was really define how

how much force needs to be applied so that that jet can go through the tissue, but not only go through the initial part of the tissue. What we wanted to understand for each part of the GI tract was how,

exactly how much pressure is required to essentially deposit some amount of drug under the surface of the tissue. So what we refer to as the submucosa or how much pressure is required to go all the way through and then use that information to really then inform what we would put in a capsule as far as

How much pressure do we need to generate and what kind of jet do we need to generate to then deposit the drug in the submucosal space in that sort of compartment to really have that maximal effect and not go all the way through the tissue. So you found out what pressure was necessary to get into the tissue in different parts of the digestive tract, in the GI tract.

But another part of this paper that I was quite intrigued by is you took inspiration from cephalopods, so squid and octopuses and that sort of thing. What was the thinking here? One aspect that I think is important here to appreciate is that the GI tract is composed of many segments, the esophagus, the stomach, the

the intestines, et cetera. And each segment has its own unique challenges when we start to think about how we might engage with that. And so what we recognize with cephalopods is that they are able to move in various directions by essentially directing those jets in certain ways. And so how we refer to the jetting elements essentially are a family of devices. For example, when you have a device that lands in the stomach, it can then give a jet from below, which

into the stomach. But if this device were traveling down the esophagus, it may be a little bit more challenging to access the side of the tissue. And so we also develop devices that

that could essentially jet to the side. So again, similar to how the cephalopods are able to direct themselves by changing the direction of the jet. How does it know which way to fire? Or is this just a aspect of the device you put in there to begin with? You're like, okay, this one's going to go in the stomach, so it's going to shoot downwards. Or this one's going to go in the esophagus, so it's going to shoot sideways. So it's predetermined at the level of the device. So the device can self-orient

And it's that self-orientation that ensures that the jetting end is in direct contact with the tissue. And how did you make sure that the jet fired, as it were, in the right place? What is activating it and setting off that jet? So within the family of devices, there are two forms or types. One of them are self-standing systems where you could swallow the capsule.

There's another one that has a side port, which is for the intestines. And then we also develop systems that can be tethered to an endoscope. And so if someone is receiving or undergoing an endoscopic procedure, now we have a way of delivering jets essentially using those tools. And so for those that are tethered, that is triggered externa.

Externally, for the ones that are self-standing, there's a few options. We can have a timed trigger where you have this capsule and at the bottom there's a little hole which is where the jet comes out. And essentially you can cover that hole with different materials. And those materials can either...

dissolve on a very fixed time scale or can be sensitive to the environment, such as an acidic environment or a non-acidic environment. And so therefore, then you start to be able to tease out or enable the delivery in, for example, the stomach

or in the small intestine depending on the pH. So you looked at a few different drugs to try this out including insulin in pigs and dogs. How much of these molecules were actually getting to the places you wanted them to get? What we found was that actually the amount of insulin that we could deliver was comparable to the administration subcutaneously or under the skin as is

is usually performed by people. So that was very reassuring. And so we demonstrated it for insulin. We also demonstrated it for an RNA molecule. And additionally, we demonstrated for a GLP-1 receptor agonist or analog, which is a molecule similar to

the drugs that I think many people are now familiar with that are being used for obesity and diabetes. So would you say that is pretty good efficacy? I would say it's more than pretty good from a success perspective. I think that the delivery of biologics, and this is the term sometimes used for this class of drugs, orally in general and currently approved products is in the single percent range.

The double digit sort of range is really what we typically see with a standard injection. And so to be able to do that with a device like,

that is administered orally, I think is really remarkable. And I think demonstrates and showcases the promise of our ability to really help patients receive medications and potentially a new route that in general, most people prefer. Now, there were some videos included with the paper that I've had a look at. And in one of them, you're looking at the inside of a pig's stomach.

and one of the devices is lying there. Then it fires out its jet and flies away from where it was. So I was wondering, is that intentional? Are they supposed to sort of ping off when they fire? Or is this something you want to address in the future? No, I think there's an important next step, which is really understanding if some of the movement that is essentially induced by the jetting is sensed by the person. And that's something, and that feedback we are unable to receive from people

the pigs and dogs that receive them. And we don't know yet. People will feel it. And if they do feel it, is it uncomfortable? Is it bothersome in any way? And what else would you say you wanted to do to improve these as we go forward? So as we continue, I mean, safety is critical to us. And part of this body of work was really delineating the performance of jets across the GI tract of a large mammal, which we've done fairly thoroughly through the study. But

translating those findings now to humans will be also important to really help delineate the safety parameters and also optimal pressures in humans. So that's one. Two, the manufacturing and scale-up is always a challenge. I mean, certainly here we are describing an early stage sort of research stage preclinical demonstration of our ability to deliver drugs using jets in an ingestible or tethered format.

And so thinking about how we build from here on manufacturing and then again on the safety, but also efficacy with respect to the capacity of these devices to deliver drug with very high bioavailability. And I have another question, but it's just basically for me. I'm just curious. So when you

were inspired by the cephalopod sort of squirting system. How did you study that? Did you watch videos of cephalopods? Did you have any in the lab? What exactly were you doing to tease out how it is that their jets were working? No, great question. And someone just asked if I had been on holiday on some diving expedition, and I wish that were the case. No. So...

You know, in the early phases of this program, together with a graduate student, we had been looking at actually several other organisms and looking at how they functioned.

essentially had these rapid triggers for similar applications and then had started sort of also thinking about jetting as a way of delivery. But rather than sort of we witnessed, you know, a squid sort of ejecting its ink and then said, oh, you know, so just to be transparent, I think it's more in parallel where we start thinking about ways of doing this and then look to nature to say, well, let's see how nature has sort of approached these applications.

or how they've applied this mechanism. But I wish it had been on holiday. That would have been cool. Yeah, that would be cool. Giovanni Traverso at the Massachusetts Institute of Technology in the US there. To read his paper, look out for a link in the show notes. Coming up, two teams of chemists describe new approaches to breaking down so-called forever chemicals. Right now, though, it's time for the Research Highlights with Dan Fox. ♪

For much of the past 65 million years, the heavy-beaked predators known as terror birds perched at the top of the food chain. Now researchers have uncovered a fossil from what might be the largest terror bird ever found. Terror birds were characterized by slender bodies and adaptations for running on land, with most unable to fly at all.

Researchers went looking for new pterobird fossils at the La Venta site in Colombia, one of the richest fossil deposits in South America. They found a piece of fossil leg bone and after analysing the fragment's size, structure and grooves, classified it as originating from a subfamily of pterobirds. They were also able to estimate the bird's weight to be 156 kilograms, about the same as a giant panda.

making it the biggest terror bird ever discovered. You can read that research in full in Papers in Paleontology. Infections of the gums have been linked with a higher risk of premature birth. But a massive study in Malawi has shown a way to reduce this. Chewing gum.

10,000 participants, most of them in the early stages of pregnancy, took part in a huge trial studying the effects of xylitol gum in pregnant people. All received oral health education and 4,500 participants were also instructed to chew xylitol gum twice daily.

The rate of preterm delivery, giving birth before 37 weeks of pregnancy, was lower in the xylitol gum group. And the authors say that chewing gum could be a cost-effective strategy to prevent preterm birth. Chew over that research in Med. This week there's two papers in Nature on a similar theme, developing new ways to break down so-called forever chemicals.

Joining me to chat about them is Brydon Labai, Senior Editor at the Nature Journal, who handled the papers. Brydon, thank you for being here. Yeah, nice to be here. So before we get into the research, let's get some of our definitions straight. What do researchers mean by forever chemicals? I mean, I'm guessing the clue is in the name somewhat. Yeah, absolutely. So these are chemicals that

persist in the environment for a long time hence the name forever chemicals this is because they contain a series of carbon fluorine bonds and this is one of the strongest bonds that we know of in chemistry and so therefore it's just really hard to break these things down so they're incredibly useful molecules for a range of different applications they've been used in you know your cooking pans for example non-stick applications firefighting foams things like that

But when they've stopped being useful, they just hang around for a long time. And that's a big problem. And obviously, you know, we're calling them forever chemicals, but they do have a proper...

scientific name, which is sort of initialised to PFASs. Exactly. So PFAS just stands for perfluoro or polyfluoroalkyl substances. And it's not just one compound we're talking about. There's over 10,000 of these molecules. And so it's the strength of this carbon fluorine bond then that gives these molecules their abilities, but also is an issue later on then. I mean, can they be broken down in terms of things like recycling? I think recycling would be quite difficult. There are methods to break them down.

but they are few and far between. Some of them have been shown to work on scale. For example, if you were to take contaminated soil with some of these forever chemicals in, you can actually do that by a process called mechanochemistry, where you essentially mill it around in a big reactor and use that mechanical energy to break these things down. That works okay. But other than that...

There are some really harsh conditions that are used to do this. A lot of the time, these things are just incinerated, which isn't very effective and obviously costs a lot of energy. So we really need some better ways of addressing this problem. And so that's where these two new papers come in then. So they've shown evidence of using light-activated catalysts to break down some types of PFAS under less harsh conditions than have been used in the past.

Why is this an avenue that researchers have been exploring? This area where we use light to power catalysis has been developing really nicely for the last 10 or 20 years or so and has had to show a lot of different applications. And what we can use here is this natural light energy where we absorb that light into a catalyst and use the energy that you absorb into it to break some bonds and

And so now these labs that are publishing these papers have shown that we can do something similar with carbon-fluorine bonds. Well, let's talk about those papers then. So in terms of breaking this carbon-fluorine bond, they come at it in slightly different ways. Now, the reactions in the paper by Zhang et al., they end up with a PFAS molecule that's kind of broken down into its constituent parts. And there's another paper by Liu et al., which essentially keeps the molecule whole permanently.

but replaces the fluorine atoms with hydrogen ones. Yes, so essentially what these studies report is these light-powered catalysts that have incredibly strong reducing potentials. So what this means is they can absorb this light energy and deliver that energy into the PFAS, into that carbon-fluorine bond.

Those electrons that are being delivered in is what allows this molecule to then break down because now it suddenly has a lot more energy in it. In one case, it's reduced down and the actual chain of the polymer or perfluoroalkyl substance is broken down to amorphous carbon. It's essentially a substance a bit like charcoal. That paper also makes fluoride as the byproducts of the reaction, which could be useful for the fluorine industry, which is a big chemical industry.

In the other paper, they are essentially replacing those carbon-fluorine bonds with carbon-hydrogen bonds. And now we're talking about the standard organic molecules that you find in any chemistry lab and are much easier to break down and also don't have the same environmental persistence problems and toxicity that we know exists with PFASs. I think what's interesting in this young paper, you say that some of the breakdown products could be used in the fluorine industry. And it seems that one of the products is an active ingredient in toothpastes.

Yeah, and this is actually an interesting side of this work because at the moment the fluorine industry creates fluoride using a very acidic chemical called HF and that's incredibly toxic.

And so having, for example, an alternative to do this, this paper may actually solve more than one problem. And in terms of how these stack up to existing methods, then let's talk about some of the conditions involved, because it's not a huge amount of heat, but you do need light. Really, these two operate what I would describe as very mild conditions. So one of them is just run at room temperature. The other is run about 40 to 60 degrees. So these are really mild conditions.

compared to, for example, the amount of energy you would need to put in in some other approaches that have been achieved. I think they're still what I would describe as being quite academic. These are still reactions that are run in organic solvents. And so while they use little energy, there's obviously a lot of work to develop these catalysts so they work in the real world and on scale.

However, what I would say is both of these studies, they talk a lot and they show a lot of work about catalyst development. And so it's conceivable that you can use that information to be built on and develop more practical catalysts. For example, that works on contaminated soils or in wastewater, where you would have a situation where you just shine sunlight on wastewater. The catalyst is in that system and it does exactly the same job as in this paper.

And so that's interesting then. So these aren't necessarily it in terms of solving the problem, but they show that this is an avenue, a direction that could be taken later on with further chemical development. Absolutely, yeah. There's a lot of fundamental work in these studies. I think these are really about just showing that this is actually something that's possible.

Even though there are similarly powerful light-powered catalysts out there, none have been shown to achieve this reaction, this breaking of these PFAS carbon fluoride bonds. And as an editor, what was it about these papers that you saw that piqued your interest? So I think aside from the applied advance in breaking down PFASes,

There's a key mechanistic component, how these catalysts work, that is really central to the advance in the papers, because this is what other researchers will be able to build on to improve these systems, make them, for example, more practically relevant, water-soluble, far more tolerant over a longer period of time, all the things that we need to actually use this kind of approach to address the environmental problem. And so you describe this work then as

And obviously, they aren't perfect in every situation in terms of yield and what have you. But also, PFASs are quite a broad church.

And I think one of these papers shows that it can break down powdered form of one PFAS, but when it's in maybe a solid form, like you might find in a frying pan, for example, it's more of a challenge. Yeah, absolutely. I mean, there's lots of challenges to overcome and translating this research to something that's going to be more broadly applicable. But I think we need these kind of ingenuitive solutions now.

to try and address this problem because it is so far reaching. And there's been various news stories about the significance and the cost of this problem. And so we really need, as well as immediate solutions now, we need solutions that are going to work in 10 or 20 years' time because these compounds are still being put into the environment and are still not breaking down. And as someone who is embedded in the chemistry world, it seems like breaking this carbon-fluorine bond

has been difficult not to crack. I mean, what do you think the wider discipline will think about this? Yeah, I hope they will see this as a really important application of a field that's been developing for some time to show that light-powered catalysts can break down something like PFASs or forever chemicals

is a really societally important application. And ultimately, this is showing that chemistry can be the solution to something that it itself has created. Nature's Brydon Labai there. You can find links to the two papers we discussed and an Associated News and Views article over in the show notes. 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.

Ben, what have you been reading this time? Yeah, I've got a story about the latest findings looking at the makeup of the far side of the moon. Now, this is something I read about on CNN's website. There's an article on Nature's website too, and it's based on papers in Nature and Science. Am I right in saying this is Chang'e 6? Yeah, absolutely right. This is China's Chang'e 6 mission, which earlier this year brought just under two kilograms of lunar soil back from the

the far side of the moon from a giant impact crater called the South Pole-Aitken-Wallace.

basin. Now, the moon is a bit two-faced, in so much as there are some significant differences between the face that we can see, the near side, and the far side, which points away from the Earth. And why they're so different has always been a bit of a mystery. So, the near side of the moon has these quite expansive pools of solidified magma, okay? Now, they make up maybe 30%-ish of the near side. The far side, they make up

And the far side is, you know, absolutely battered by impact craters. And there's differences in the topography, in the crust thickness, all this kind of stuff. And trying to figure out why, as I say, has been unclear. And that's where this research comes in from two independent groups. So what did they find? Yeah, they've been looking at fragments of these structures.

soil samples. It's vanishingly rare samples from the far side of the moon then. And they've been looking at what's there and dating it using a special sort of isotope dating between two types of lead. A bit similar to what we talked about last week. Similar but different. And they've looked at basalt, this volcanic rock, and they've dated it back to around 2.8 billion years. Okay, so this was formed by cooling magma. And

And 2.8 billion years, whilst that seems like a very, very, very long time, it's actually quite recent in the scheme of things. Is it?

it? Yeah, no, it is. So this is very different to the volcanic activity seen on the near side of the moon, which was dated using soil samples taken from things like NASA's Apollo missions and Russia's lunar missions. And these samples are thought to be over 3 billion years old, which makes this result of 2.8 billion years ago more recent, meaning that the moon was maybe more volcanic and more molten, certainly on the far side than previously thought. That's fascinating. So one side was

still having volcanoes and explosions while one was settled down? Well, to be honest with you, it gets quite complicated, as I'll explain in a bit. And one of the mysteries that has come out of this research is what's powering this far side volcanic activity, okay? So the most recent samples, these 2.8 billion year old samples from the far side of the moon, they weren't very creep rich samples.

Sorry, creep rich. So creep, K-R-E-E-P, stands for potassium. Obviously, K is its chemical element. Rare earth elements and phosphorus. Now, this group of things, this creep is radioactive and heat producing. And it's thought that this helps explain volcanism on Earth.

the moon, certainly on the near side samples have been found that are quite creep rich and it's thought that this heat keeps the magma flowing, keeps the volcanism occurring. But so here we've got this situation where on the far side of the moon,

There is evidence of volcanoes, but in a creep-poor area. So what's powering the volcanoes to be volcanoes? I think the answer is currently shrug. Excellent. More work to be done. Well, it turns out there's a lot we don't know about our nearest neighbour. For example, it seems like

The volcanism on the far side may have gone on for a very, very long time, you know, maybe a billion and a half years, because in the samples from Chang'e 6 that were analysed, there was a fragment which was dated to 4.2 billion years old. And as I understand it, was...

creep rich. So we have this extended period of time where there's a whole lot that we kind of can't understand just yet. I guess we don't actually have that many data points from the moon given the number of missions that have actually got there. Well I think that's a fair thing to say and I think a lot of what researchers have put forward about the way the moon was made and about you know its activity have come from looking at these Apollo samples. So now we have this other side of

And I think what muddies the waters even more is that Chang'e 5, which is the previous Chinese mission to the moon, found evidence of nearside volcanic activity only two billion years ago. So I think that speaks to we need to know a lot more about what's going on in different places to really understand, say, how the moon formed. Well, hopefully this is the first of many papers to come out around these samples. I mean, you'd imagine so. So these samples only came back to Earth earlier this year.

this year and obviously they're very very precious and you know researchers are very very keen to get their hands on them to find out say what makes the moon tick I suppose yeah absolutely oh I look forward to that well thank you Ben I'll bring it back down to earth for this one I've been reading about tomatoes right and as the quote goes knowledge is knowing that a tomato is actually a fruit wisdom is not putting it in a fruit salad I think it's something

along those lines. Yeah. So this is actually talking about the sweetness of tomatoes or more specifically a genetically engineered tomato that is big and sweet.

So normally, if you think about a large tomato, the kind you might buy from a supermarket, you don't tend to think of them as being particularly sweet. They tend to conjure more images of watery, I would say, particularly. And actually, it's been proved that the larger a tomato is grown, it is genetically linked to be less sweet. Right. So the other end of the scale, you think of cherry tomatoes, they can be very, very sweet indeed. So presumably, there is a sweet spot, so to speak, between those two. What's going on with the bigger ones?

So they found that in producing by genetically selecting these larger variants of tomatoes, they're up to 100 times larger than wild tomato ancestors. The bigger the fruit, the lower the proportion of sugars that give you that kind of

homegrown tomato taste. And researchers compared the genomes of these cultured tomato species with wild and sweeter counterparts. And they found that the sweet spot, as it may be, in two genes that each encode a protein that degrades the enzymes responsible for sugar production. Okay, so presumably by reducing the activity or completely stopping those enzymes, you can get

sweeter tomatoes. Exactly. And that's exactly what they did. They turned off, they deactivated these two genes using CRISPR. And they found that the plants bore fruit that was much sweeter, but still just as large. In fact, there were 30% more levels of glucose and fructose in these fruits compared to their non-gene edited counterpart. And did they let people try these tomatoes? Yeah, they let 100 volunteers taste these tomatoes.

and they were identified as being significantly sweeter than the regular old counterparts. All right, so we have these engineered tomatoes then that are sweeter and that can

consumers enjoy eating. What happens now? Well, yeah, they'll not only taste better in your sandwich, but there's another benefit. It could cut the amount of time, energy, money that goes into preparing other products that come from these tomatoes, like tomato paste, for example, because normally you're taking out water content in order to increase the ratio of sugar. And so these could actually speed up processing times, make them more efficient, both with energy and money. And so the team have found these proteins then that interfere with sugar production.

Obviously, you can think of a lot of different sorts of fruit and vegetables that you might want to be sweeter. Is this possible, do you think, for other things? Have they said anything about that? Yeah, they're found across a range of plant species. So that is one of the things that they're going to be looking into in the future. Well, listeners can't hear my stomach rumbling, but before they do, maybe we should call it there for this week's

briefing chat and listeners for more on these stories and where you can get more like them delivered directly to your inbox check out the show notes for some links that's all for this week as always you can keep in touch with us on x we're at nature podcast or you can send an email to podcast at nature.com i'm emily bates and i'm benjamin thompson thanks for listening

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