Medicinal microbes for kidney stones, and musky mice

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1:04Absolute genius. Get this. Welcome. Welcome. This is the show where we bring you science. What that essentially means is... Discovery is... Advances. Questions. Research. Technology. Unbelievable. Without further ado, this is The Naked Scientist. Hello, welcome to The Naked Scientist podcast, the programme that brings you the biggest breakthroughs and talks to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith. On the way, why a dose of bacteria might be the solution to combating kidney stones, what tooth enamel can tell us about the lives and diets of dinosaurs, and what the world's most abundant insects can teach robots.

1:42From Cambridge University's Institute of Continuing Education, this is The Naked Scientists.

1:55Kidney stones are small, hard deposits that form, as their name suggests, in our kidneys. They develop when waste substances in urine build up forming crystals. Those who've had them will know that if bits break off they can cause severe pain, they can lead to infections and in extreme cases they could even obstruct urine flow. But scientists in America may have a solution. One of the commonest types of kidney stone is formed from a build-up of the substance known as oxalic acid or oxalate which we pick up largely from our diet. so what Wes Whittaker from Novone Biotechnologies and Stanford University School of Medicine has done is to engineer a species of gut microbes so it becomes much better at breaking this stuff down before it gets into the body the idea of course is to produce a probiotic that could cut your risk of kidney stones forming in the first place what we're focused on is a disease called enteric hyperoxylurea and that is when a chemical called oxalate which is part of a normal healthy diet found in nuts and vegetables can be overabsorbed in the gut.

3:06And then it's concentrated in the kidneys and combined with calcium to make these calcium oxalate deposits, kidney stones. About 80 % of kidney stones are made up of calcium oxalate. There are a number of reasons why that could happen. But one of the common ones is having underlying GI disorders such as Crohn's disease or gastric bypass. And in those cases, for example, fat malabsorption could lead to calcium, where it gets sort of trapped with the fat that doesn't get absorbed because of these issues in the gut. And normally, the calcium would bind with the oxalate chemical in the gut and sort of form a solid deposit there and just pass through and be harmless.

3:45But when the fat binds to calcium, now the oxalate is sort of free to get absorbed. And that's why it ends up concentrated in the kidneys. In essence then it's giving an enriched population of microbes that have the genetic and metabolic know-how, I suppose a biochemical knife and fork that will dismantle oxalate in the gut so that you can't absorb it and turn it into a kidney stone. That's exactly right. How have you done that then? We started off with very common bacteria in the gut of most people called Pockei colo vulgatus and we made three changes to it. The first is we wanted to be able to get our bacteria to colonize the gut well.

4:22And you can imagine the gut has hundreds of different microbes that our bacteria would be competing with, and it could vary person to person. So we wanted that to be more reliable. And so we engineered in the ability of our bacteria to use this polysaccharide, this nutrient called porphyrin, which is found in red algae, and you won't find it in terrestrial plants. Most of us don't have any bacteria in our gut that are capable of using that nutrient. So when we feed that nutrient, we're basically feeding just our bacteria, which is very simple, and that's important for getting it to work well. We also modified our bacteria so that it is really dependent on that porphyrin molecule, so that just genes that are essential for it to be able to grow just don't function in the absence of porphyrin, so that the bacteria won't grow outside of the patient or treatment period.

5:07And finally, we engineered the bacteria so that it's able to perform the therapeutic activity. And in this case, like you mentioned, it's just the ability to break down this oxalate. We added five genes for the breakdown of oxalate which the bacteria don't normally do but we were able to get them to be able to rapidly perform that activity. But do you absorb oxalic acid oxalate from the colon? Because my understanding is we only pick up water from there so how can they exert much of a therapeutic effect if your small bowel which does most of your absorbing heavy lifting has already got all the oxalate out and into your bloodstream?

5:37Yeah that's a great question so there was some unknown about whether or not the colon was the primary place to absorb and we talked to a number of experts and GI doctors and we think there is a lot of evidence for that. One of the pieces of evidence is that the bacteria, this oxalobacter, normally breaks down oxalate. Its absence from the co-limers that primarily resides is a risk factor for this hyperoxyuria disease. Ah, so even though some absorption can happen in the small gut, there's still a lot going on in the big bowel as well and hence if you put the microbes at the right place at the right time, they will break it down and reduce the amount you've got circulating.

6:16Therefore, you make kidney stones less efficiently. That's exactly right. And is that what happened? Did you see that people demonstrated lower blood levels and lower kidney levels of oxalic acid when you did this? Yes, we saw that in some patients we lost the ability to break down oxalates. There's room for improvement. But we did see a reduction in urine oxalate in patients, which we're quite happy with. But this was done with a small number of patients. We need to do this with a much bigger study to be really confident. So at the moment, you know that it has the potential to work. There's a bit of tinkering to do to improve the efficiency.

6:51But would the reduction in the amount of oxalate in the urine be sufficient to reduce the risk of developing stones? Or is the difference statistically significant, but it wouldn't make a clinical difference? The oxalate in the urine reduced about 20-25%. And there's some evidence that the concentration of oxalate in the urine is proportional to the frequency of getting kidney stones. So we think that it would be helpful for these patients that have recurrent kidney stones. And there have been some other companies that have come before us looking to treat this disease and have had previous endpoints being a percentage of patients that achieve at least a 20 % reduction in urine oxalate.

7:33So we do think it would be clinically meaningful. we've been familiar with the idea of the transpusion the idea of giving people say colonic washings to deal with problems like clostridium difficile the hospital superbug that you often get that when people take too many antibiotics and it saves lives doesn't it so you're actually going a step further and adding discrete microbes to solve discrete problems is this really you think the beginning of a quite a fertile avenue are there going to be a range of possible disorders that we could treat by giving people bacteria paradoxically to treat a disease yes yeah i think you're exactly right that is our hope that um here we'll establish just a really reliable way of adding defined activities to the gut and then you can imagine swapping out that oxalate degradation pathway with any therapeutic activity for instance you could secrete proteins that bind to the toxins of the bacteria as a way of preventing them from being able to cause diseases or go after something like inflammatory bowel disease, where there may be a number of different proteins or pathways you might want to add to be able to influence that disease.

8:38And we're hoping this is really a platform for being able to take those approaches in the future. Wes Whittaker at Novone Biotechnologies and Stanford University School of Medicine. That study has just come out in science. To the social pecking order now. And researchers at the Francis Crick Institute have shown that mice can use chemical cues, including odours to detect the social rank of an unfamiliar mouse and compare it with their own. They use this information to determine their behaviour. Speaking with James Titko, Johnny Cole. Social hierarchies are well studied in males. What we know is that when we house males in cages, you can quite easily tell who's the top mouse and who's the bottom mouse.

9:21And in order to get a quantitative reader out of that, there's a number of ways. And one way that we can use is the so-called tube test, which creates a very easily quantifiable binary readout of who's higher in the hierarchy between any two given mice that you're testing. So talk me through how that works. What are you actually observing in those experiments? Yes, so it's an extremely simple test. You basically have a transparent plexiglass tube. It's about 30 to 50 centimeters long, open on both ends, and you basically introduce one mouse at each end at the same time. And then the mice will crawl forward in that tube.

9:52The tube is too narrow to turn back, so they will have to actually reverse out. But what happens if they meet in the middle, some decision making takes place and one mouse ends up pushing out the other mouse from the tube. That's how we then score the relative hierarchy, you know, so that the winner is the one that pushes the loser out of the tube. For a mouse to know how to behave in this tube, whether to press on or retreat, I suppose it has to weigh up two bits of information, its own standing in the social hierarchy and that of its opponent. Do we have a handle on how mice understand this?

10:23Absolutely. These are the two types of information that you need. And what has happened a lot in the field is that we've reached a reasonably good understanding of how your own position in the hierarchy is encoded in the brain. And we've also found ways to artificially boost that rank by stimulating an area of the brain called the prefrontal cortex. But what has been lacking is how mice figure out the status, the rank position of their opponent. So that was the, I guess, the critical knowledge gap that this study addressed. So how did you go about probing that question? Okay, if mice know how to behave in these confrontations, it might be because of one of two things.

11:02It might be because they know their opponent. They've lived together for many months. You know that this mouse is going to behave that way. And the hierarchies are stable because you know who you're dealing with. The other explanation would be that there are general signals of hierarchy that mice can use to make an informed decision in this tube test. So the simple experiment that Nevin, who was the first author on this study, did is he established a hierarchy in one cage and then made sure this hierarchy was stable. But then he tested the mice of that hierarchy with complete stranger mice that also had an established hierarchy.

11:34And that was very revealing because what we found, and I'm still surprised by how well this worked, is that mice could behave in accordance with the hierarchy of stranger mice. So that they knew exactly who they were dealing with, even though they had never seen these opponents. So the question then becomes, how are they doing this? What sort of cues are they using from the other mouse to be able to determine how they should behave? So there's a few simple ones that we could rule out. So for instance, we did these experiments in total darkness using night vision goggles. And we found that mice can still perfectly do this and they can still infer the rank of complete strangers.

12:09The mice weren't in night vision goggles, you guys were in night vision goggles. Sorry, just to clarify, we were in night vision goggles. These experiments are actually quite challenging because depth perception with night vision goggles is extremely limited. But anyway, so it's not vision. So what's next? We knew that mice are extremely chemosensory creatures. They rely a lot on smell and perception of pheromones, for instance. So next, we tested whether some form of chemo signals might be necessary for this behavior. So mice, as many other mammals and vertebrates, they have two major types of chemo signal detection systems.

12:40One is the normal olfactory system that detects volatile cues, so odors. But then they also have a second system, the vomeronasal system, that detects contact chemosignals, chemicals that are not volatile. In order to detect those, you really have to be in physical contact with the source. We therefore next independently ablated either of those systems. And what we found was then when we ablated or abolished either of those systems, nothing happened. The mice could still completely and confidently infer the rank of strangers. But then the surprise happened when we ablated both of them at the same time.

13:11Then their performance was completely random. So that really tells us that either of those chemosensory system is sufficient for this rank generalization. Absolutely fascinating. It begs the question then, what's the mechanism here? What are the chemosensory signals that they're receiving? How are they being processed in the brain, which I imagine very much interests you as a neuroscientist? Have we got anywhere to answering those questions? Yeah, so absolutely. The nature of these cues is the next frontier. We know a bit. For instance, one experiment that we did is that when you take urine from a rank one, an alpha male, and you apply this to a lower rank male, this can actually then boost the perceived status of that lower rank male and it can increase its status.

13:57Converse, you're rubbing their urine along the other mouth. Yep, exactly. That's what we do. Not my first choice of cologne. Yeah, no, these are fun experiments that you probably want to do once in your life and then never again. And the interesting thing is that conversely, when you do the opposite experiments, you take urine from a lower ranking mouse and apply it to a high ranking mouse. That doesn't lower the status of the high ranking mouse. So that means that we have some sort of chemical scalable dominance cue. So it's the more of it you have, the more dominantly you are perceived by other mice.

14:29Now, what's the nature of these cues? We don't know. We know based on our lesion studies, there might be a number of different chemicals, some of which are volatile and some of which are non-volatile. And I guess figuring out what they are is non-trivial, but that's absolutely, that will be the next step in this sort of question. James Ticko and Johnny Cole at the Francis Crick Institute there, and that study has just come out in Current Biology. Hi, it's Paige from Giggly Squad, and this episode is sponsored by Experian Boost. Summer glow-up? Check. Credit glow-up? Even better. Boost your credit scores instantly by getting credit for bills you're already paying.

15:07Your phone, utilities, rent, and insurance. I wish dating kind of worked like that. Connect your bank account, add those on-time payments to your Experian credit file, and your FICO score updates right away. You could instantly raise your FICO score by an average of 14 points with Experian Boost. Download the Experian app for free today. Results will vary. Users who received a boost improved their FICO score 8 from Experian by an average of 14 points. See App Store or Experian.com for details. Results will vary. Not all payments are Boost eligible. Users who received a Boost improved their FICO score rate from Experian by an average of 14 points.

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16:13Music in the programme is sponsored by Epidemic Sound, perfect music for audio and video productions. This is The Naked Scientist with me, Chris Smith, still to come what robots can learn from an ant's grip. But first, a new study has used advanced analysis of fossilised teeth to uncover amazing details about what a group of long-necked dinosaurs called sauropods ate, where they lived and how they might have moved around during the Jurassic 200 million years ago. Daniela Winkler at Keele University is one of the scientists behind it. We wanted to find out how the sauropods, so the long-necked dinosaurs that were like the largest creatures that ever walked on the earth, how they lived together in certain environments and if they fed on the same staff so that they were in competition with each other or if they actually split the resources they found, so the food, to coexist in these environments.

17:12So you're saying as a group, different members of the group would eat one thing, different members would eat another and therefore everyone's a winner because you're not conflicting or competing in what you're trying to exploit. Right, that's the idea. So we want to know if different species have their specific taste for different plants, and so they don't compete. And how can you work that out, given these things were around tens of millions of years ago? We look at the best preserved fossils we have from sauropods, and that are their teeth, because teeth are from the hardest material in the body, and they are super well preserved in the fossil record.

17:48They are so well preserved that they even show tiny, tiny scratches, So tiny wear marks that stem directly from the contact with the food. So when they chew, they slightly wear their teeth. And how they wear their teeth depends on what they ate. And the whole pattern gives us a very distinct idea of what kind of plants they ate and also in what kind of environment they actually lived because other stuff in the environment is also interacting with the teeth. For example, dirt, grit, dust. because that may settle on the plants from time to time, especially if it's a very dry environment. And then the sauropods can't help but just also munch on the dirt that's on the plant, and that leaves additional small scratches.

18:34Are they in competition, or are they actually going for as diverse range of foodstuffs as they can get? So we found that when we analysed these three very different environments, one in nowadays United States of America, one in today's Portugal, and one in Tanzania and Africa. So the really cool finding we got was there's this one group of dinosaurs that are called Camarasaurids. So one of the famous dinosaurs is the Camarasaurus. I guess many people maybe have heard about it already. And the Camarasaurus was around both in Portugal and also in the US. And we found that it had a super, super narrow diet range it fed on.

19:15So it was super selective. It had a very, very distinct wear. And that is super uncommon because imagine we are analyzing fossils. They may have been deposited. So maybe these animals died over the course of hundreds of thousands of years. So they are not all from the same exact time mark. But these Camarosaurids, they showed such consistent wear on their teeth. that we think that they were very, very, very specialized on a specific diet and that they even followed this preferred food source seasonally. So if it was not available in their habitat anymore, they might have migrated. Doesn't being so fussy make them highly vulnerable?

19:57Very likely. So I think that had made them sort of vulnerable. And we see that their specific, very narrow diet also differed slightly between the United States and Portugal. Because in Portugal, there was another species of sauerpods around, the Tereosaurus. And they seem to have preferred the same food sources as the Camarasaurids. And so the Camarasaurids had to slightly shift their food to avoid the competition with the Tereosaurus. But they seem to have been better in the competition so that they could force Camarasaurids into this other diet. amazing window into the past what you've unlocked here isn't it the other intriguing thing you mentioned was that the dirt and dust that's on the plant material also imparts almost like a fingerprint tooth wear pattern so you're also seeing past climate dust dryness and so on are there any intriguing possibilities emerging from that or are you seeing things that we've previously not had an opportunity to study through that.

21:02Yeah, definitely. We found that the sauropods from Tanzania, they showed like a very, very different wear pattern compared to all other species in our study. And we were kind of surprised by that because they are from a group called Brachythaurids. So very, very tall, very, very long necked animals feeding probably in the canopy, So in the high trees. And it was kind of surprising that they were so different in Tanzania. And so we looked a bit into the available climate record and we actually found that there was a huge desert belt very close to the area our dinosaurs lived. And it's very likely that sand was basically blown onto the plants and they had to munch on it when they fed.

21:50They couldn't really avoid it. And it's something we see today in the African savannah, for example. And that's exactly what we found in the dinosaurs from Tentaguru in Tanzania. So it's really cool if we have these different methods that help us to better reconstruct the past environment and climate. Daniela Winkler at Kiel University, and that study's just come out in Nature, Ecology and Evolution. Robots are already revolutionising our world, from medical procedures through to construction. But there's one aspect in particular that dexterous robots struggle with, a strong and steady grip. And in a bid to resolve this, a group of scientists in Edinburgh have taken inspiration from one of nature's most resilient and ubiquitous inhabitants, and that is the ant.

22:37Marushka Subban travelled to the Scottish capital to get to grips with this breakthrough. I've always been amazed by ants. Not just the marching, it's what they carry. A single ant can grasp and lift objects many times its own weight, with nothing but two tiny jaws. But what if a robot could do the same? Today's story takes us from the forest floor to the robotics lab, where researchers are turning ant anatomy into cutting-edge gripping technology. It's called AntGrip, and it could be the future of robotic hands. And it's all happening at the University of Edinburgh's Biorobotics Lab, part of a wider push through UKRI's Technology Missions Fund to rethink how machines interact with the world around them.

23:22To understand the inspiration behind AntGrip, I spoke with Professor Barbara Webb, the scientist who spent decades looking to insects for engineering insight. So there are many, many robotics applications that we could have if we could get them to successfully grasp objects. So robots have improved and been used in a lot more context, but it still tends to be a very controlled environment, such as a factory, or they've improved a lot for their navigation, so they're used for inspection tasks. But if the robots can actually interact with objects, they could do a lot more things. You can think of mining, you can think of environmental cleanup, agriculture.

23:59There's a lot of different areas where flexible and robust ability to grasp objects could be useful. And why ants specifically and not any other type of insect? Partly because we already studied ants, so we're familiar with them, but also because ants do handle a huge variety of objects. So many ants are generalists in what they eat, so they'll collect and take back to the nest a huge range of things, from seeds to bits of other insects to water to lots of different objects. Within the nest, they handle their own larvae and eggs, so they have to deal with soft objects and not damage them. They also build their nests by moving lots of dirt and other structures around.

24:43So there's lots of different things that they can interact with using the same mandibles as their grasping tools. It's a pretty compelling case, I would say. So how does the tech actually work? Well, if you were brave enough to put your eyes close enough to an ant's jaw, you would spot tiny hairs in its mandibles. Like how the zigzags of a snowshoe allow for better grip on the ice. A thermoplastic polyurethane version of these hairs could hold the key to a better robotic grip. To find out more, I met with the researcher who built it, Mohamed, a postdoc in Barbara's lab. The usual two-fingered grippers are usually bulky a little bit because in order to grasp, really, you need to have soft pads.

25:25And these soft pads are usually very thick because you have to have some interaction with the object you are grasping. What we are having here is a bit different. Thanks to the hairs inspired by the ants, we can have those pads, but very thin, because the hairs are doing all the increasing the friction with the object. But at the same time, it is not making the gripper bulky so that it can fit into very tight spaces. And here we are targeting warehouse automation and grasping from shelves and stuff like that. Okay, so it's a specifically two-finger gripper. So if you could explain to me, how does this piece of tech work?