Animal handedness, diabetes and dinosaurs
This month, diabetes and the body clock, the antibodies we raise to Covid-19 vaccines versus infection, dinosaurs armoured like tanks, baboons catching up on sleep, and how language evolution goes hand in hand with handedness...
In this episode
00:31 - Diabetes and the Body Clock
Diabetes and the Body Clock
Joe Bass, Northwestern University
People often say that time rules our lives; but time, it turns out, also rules the pancreas, because the function of the body clock - or circadian rhythm - is tightly linked to the release of the glucose control hormone insulin. And, by tracking the two systems, Joe Bass, at Northwestern University, has been screening drugs to find molecules that can manipulate insulin levels by tweaking the action of the clock…
Joe - A number of years ago, we began to investigate the connection between the body's internal clock and organs in the body that respond to the clock and are important in maintaining energy balance and metabolism. One of the organs is the pancreas. A surprise for us was the discovery that the very same mechanism that causes us to wake up each day also induces the pancreas to produce insulin, which controls blood sugar. So, the real purpose of our work has been to try to understand, at the most basic level, what are these connectors that links the sleep cycle to the release of insulin.
Chris - And I suppose it's not a coincidence that we know that diabetes, or at least an exacerbation of diabetes, and sleep deprivation slash when people sleep at the wrong times and eat the wrong things. They're all interlinked, then?
Joe - That's right. We know from epidemiologic studies that there's an association between things like shift work and even exposure to blue light at night which occurs when you spend a lot of time on computer screens. That kind of light triggers the brain to think that it's daytime even when it's night and it scrambles the signals internally that normally align our sleep cycle and all of our physiology with the light/dark cycle with the rising of the sun. And one of the key things that gets scrambled is the ability to metabolise sugar.
Chris - So is it that the pancreas knows the time and is doing this itself, or is there literally a connection between what the brain is doing and what the pancreas should be doing?
Joe - The problem, like many things in science, doesn't have a simple answer. Both connections are present. In other words, under normal conditions in evolution, in the context of the wild so to speak, normally, the brain sends signals to the pancreas that entrain the pancreas to function at the right time each day. However, the pancreas has its own internal clock. We believe that one of the things that happens with, say, shift work is that it's the alignment between that brain clock which responds to the light cycle and the pancreatic clock that become misaligned. So, if we understand how the clock works within the pancreas, we may begin to identify pathways that we could manipulate to realign or fix the broken clock.
Chris - And how did you go about doing that?
Joe - Well, the first thing is we have to have the tools to measure both the clock and its output. We use genetic approaches to insert what's called luciferase, which is an enzyme that's normally made in fireflies. We took a small piece of that gene and stuck it in the middle of insulin, which is the major hormone produced by the pancreas that controls blood sugar. Now, when we do that, that means that every time the pancreatic cells, the beta cells, are stimulated to release insulin - and they are stimulated primarily by glucose but also by other metabolites and molecules - every time the cell is stimulated, we have an instrument that can detect the release of the luciferase enzyme. So, instead of having to measure insulin, we measure luminescence from this luciferase.
Chris - And how do you line that up with what the clock is doing?
Joe - We take another approach using genome editing to go into the genes in the beta cell and twist around the core genes that control the clock to either eliminate or alter the function of the clock mechanism. And with those two instruments, we can now, in a very high throughput way, screen thousands of compounds to ask, "Do any of the drugs that we have in our libraries influence the release of insulin when the clock is not working?"
Chris - Did you find any?
Joe - We found a number. We screened about 3000 known drugs. Among these, we identified a handful, and then we used a number of criteria to further select those that we would advance to studying in the animal.
Chris - Any that are in common parlance or any we'll be familiar with?
Joe - One of the main hits that we had is a somewhat infamous drug at this point: it's called ivermectin. It is an anti parasitic drug, and it acts on a special ion channel in an infectious organism that is unique to that animal. But, it turns out that it's in a class of what we call metabotropic receptors, and those receptors turn out to be abundant in the pancreas. And so, for reasons that we don't entirely understand, this molecule is activating a chloride channel that's expressed within the pancreas, and that chloride channel is an important target of the clock. That was a surprise for us to find.
Chris - So the chloride channel is affected by the clock and that in turn affects the secretion of insulin. So, therefore, you've now got a molecule that can affect the output of insulin from the pancreas when the clock goes wrong. So if you've got people who've got clock related metabolic syndrome, you could potentially give them this. It might put things right?
Joe - What we would do is use this as a so-called 'scaffolding' to give us molecular insight; both into the kind of chemistry that could be used to target the pancreas, and also those molecules expressed in the pancreas that are regulators of insulin release. That latter idea that this set of receptors are insulin atrophic, which means that they induce the release of insulin, is something that we found to be interesting, and there's evidence in the literature for this. There's also evidence that in obesity, for instance, there may be substances that are produced in fat that interfere with the function of this particular channel. So it's an entire range of factors that control insulin that we stumbled upon and they appear to be controlled by the clock system.
07:24 - Animal Handedness and Language
Animal Handedness and Language
Adrien Meguerditchian, Aix-Marseille University & Yannick Becker, CNRS
Humans are unique in using speech, and the shapes of our brains reflect the fact that on the left side is a bulge corresponding to the generation and decoding of language. The fact that most people are also right handed - meaning their left brain hemisphere is dominant - has led researchers to speculate that language goes hand in hand with handedness. And that struck a chord with Adrien Meguerditchian early on in his career when he was out studying our close relatives, the baboons…
Adrien - We watched the baboons making communicative gestures and I remember having these baboons come towards me and start to threaten me. He was a young baboon. He was slapping his hand towards me and looking in my eyes and would repeatedly slap his hand. I was not moving away, I was just staring at him and he just kept doing it. This message was not working obviously because I was still around and he started to shake his head, stand up and all this display was very silent. He was only using his hand, his body posture to try to make his point. This study started from there. I remember from my PhD starting to measure which hand the baboons were using when they were communicating with his hand. I remember having an expected surprise that when the baboon was using the hand for communication, something happened in the hand preferences. You can be right-handed or left-handed when you manipulate objects, but here, when they started using gestures for communication, the use of the right hand was exposing. It was a very strange phenomena and we were wondering 'why?' It was a case even in left-handed baboons, they were using more of the right hand for communication.
And that’s what Adrien and his student Yannick Becker have since gone on to study, confirming that they principally use their right hands when they make gestures and other signals, and also that their brains too are asymmetrical towards the left, like ours. So might this be a tantilising glimpse into the evolutionary origins of our own ability to communicate? Yannick takes up the story…
Yannick - There's something peculiar about language in the human brain. It's processed more in the left side of the brain than the right. When we want to study the evolution of language, we have to look at our primate relatives or cousins; which in this case is the baboon and particular species of all monkeys. Adrien, my supervisor, has observed that these baboons use their right hand for communication more than the left hand and the right side of the body is controlled by the left hemisphere. Because language in humans is controlled by the left hemisphere, there was suddenly the hypothesis that maybe, in these baboons, it might also be the left hemisphere that is controlling communication, especially gestural communication.
Chris - That's intriguing; to think that you've got that potential asymmetry going on in these close human relatives. Do they have right hand dominance like we do though? Because in humans, 90% of the population are right-handed and the vast majority of those right-handers are controlling their right hand with the left side of their brain, which is also where language is, which is why we have this hypothesis about left side dominance of the brain. Is that the same with handedness in these baboons?
Yannick - It's very close. We divide handedness into two different ways of assessing handedness. There's this what natively would call handedness maybe in the humans that we use actions with our hands. For this baboons are, on a population level, a little bit right handed. But then when we assess handedness for communication, special gestures that they make to communicate with each other, they are much more baboons right-handed for communicative gestures. Even those that have been left-handed in these manual actions will become right-handed in communicated gestures.
Chris - What sorts of gestures do they make then? How do they signal to each other with their right hands?
Yannick - There's this hand slapping gesture. They slap one hand to the ground in order to intimidate; it's really a threatening gesture. If you see this, you immediately understand that this baboon tells you to go away. There's a whole body posture that comes with it.
Chris - Is your sort of inference then that, given that gestures are all about communication, and in humans a chief mode of communication is speech, and we know speech is in the majority of us is on the left side of the brain, that perhaps this is one step along the road to which our brains evolve the ability to speak because they had inherited this particular use of one side of the body for communication that we've taken it a step further?
Yannick - That's exactly the point. Yeah. Thank you. We have inherited something in our evolutionary history from our ancestors, and this can be also found in these baboons. This asymmetry for this kind of communicative gesture might be a precursor of what we call language now.
Chris - Have you done the experiment you would do on a human? If we put a human in an MRI scanner and asked them to speak, we can see relative activation on the left side of the brain where they're creating that speech. Can you do a similar sort of thing in your baboons to see if they are similarly using that part of the brain asymmetrically when they're doing this communication?
Yannick - Yeah. That's the holy grail to get functional brain scannings. It's very difficult to do in animal primates, so what we've done is we're scanning these baboons, but they were asleep, we have anatomical scans, and then our function would be the behaviour that we have recorded.
Chris - And how does the anatomy compare left and right in the animals?
Yannick - We can measure some regions of interest in both hemispheres, and then we can compare them and calculate what we call an asymmetry quotient. We have done this study for a very special area that was shown to be an equivalent area to this famous speech production area in the human brain, which is called 'broca's area'. Compared to the left and the right hemisphere, we saw that this fold will be deeper in the left brain for those subjects that were communicating with the right hand, and reversibly, it was deep in the right atmosphere for those that are communicating with the left hand.
Chris - That suggests that there is this specialisation that does seem to be associated with communication, but going back to the humans again, we know that about 10% of humans are left handed, but they still do language a lot of the time on the left side of the brain. Did you find any baboons that bucked the trend like that and were lefties, but also appeared to have the specialisation for possible language still on the left?
Yannick - Very, very interesting question. We have variation in our data, but I think the most important point for us is that in humans, we find this for this manual action handedness. The hypothesis is that we would find this less if we assess handedness for communicative gesture also in humans, but this has never been done yet.
15:17 - When do baboons catch up on sleep?
When do baboons catch up on sleep?
Carter Loftus, UC Davis
Sleep appears to be life critical. Deprive a human of it and they suffer metabolic and psychological consequences. Some animals even die if they're sleep deprived for long enough. And, as most new parents know, given the chance, we can catch up on lost sleep by sleeping for longer later. But what about in the wild, where the pressure of daily life might not afford a sleep-robbed animal the opportunity to catch up? Do they go without? That's what Carter Loftus has been trying to find out in Kenya's baboon population...
Carter - There's this homeostatic sleep drive. After animals experience particularly poor quality sleep, they respond to that by sleeping better the following nights: longer and more intensely. But in the wild, animals face a lot of competing priorities; predation, they have to find resources, and we really don't know anything about how animals in the wild navigate between having to invest in sleep and social and ecological priorities.
Chris - So really, the gold standard is: you're robbed of sleep, you make up for it in some way. But, because we have very artificial circumstances when we're doing the sorts of studies that inform how animals and humans take sleep, we don't capture that tension in the way we do those studies?
Carter - Exactly. The vast majority of studies of sleep have occurred in the laboratory or at the bedside where these external factors that might shape our sleep are intentionally removed. But what they remove are the ecological and social pressures that may be really influential on the way that sleep has evolved in the environment in which it actually evolved.
Chris - Presumably, part of the reason why those are not captured is because it's actually quite hard to do this, I would think?
Carter - It is. And the gold standard for studying sleep research is polysomnography which requires intracranially or subdermally implanted electrodes that can measure brain activity. That's where we introduced a new method of using accelerometry to try to noninvasively answer some of these questions about how animals balance their need for sleep in the wild.
Chris - Accelerometry, that's basically capturing movement. Are you using movement as a proxy for how awake an animal is and, therefore, when they're not moving, they must be asleep?
Carter - Exactly. We're essentially looking for periods of sustained inactivity, and then we're validating this measure of sleep against thermal video that we have of sleeping baboons in the wild.
Chris - Which baboons were you studying and how do you capture that movement from them?
Carter - We were studying a group of wild olive baboons in Laikipia, Kenya, and collared greater than 80% of the adults and sub adults in the group with GPS collars that had an accelerometer unit implanted. Then, these accelerometers collect essentially all the movements that a baboon does for the duration of the study, which was around 30 days.
Chris - That's powerful because that tells you what they're doing and where they are when they're doing it. So, presumably, you can also get the proximity. You can look at where they are in relation to each other as well?
Carter - Exactly. That's something that we looked at as well as several other GPS derived metrics that we were able to pull from the data, such as how far they travelled on a given day, where they slept, where they slept in relation to their group mates, and how all of these variables actually had an influence on their sleep patterns.
Chris - The reason I brought that up is because, obviously when we do sleep studies, often we divorce people from other stimuli, including each other. So, being able to study how groups affect compensatory sleep, or sleep behaviour, is quite insightful. So, were you able to capture that in this study?
Carter - Yeah, we were. I think that was one of the most exciting findings of this study is that the collective dynamics that animals experience when they live in groups, really continue into their sleep period. We found that the baboons that we studied actually synchronised their periods of nocturnal awakening, which is actually quite in contrast to a lot of predictions which suggest that animals should really stagger their periods of nocturnal awakening to maximise their collective vigilance and be able to hear and see predators when they're coming as a group.
Chris - What did you actually see then? You tracked these baboons, you've got the whole lot over a really nice long period of time so if there are periods when they're robbed of sleep we should see compensation, etc. You've got the group dynamic: what trends and what patterns emerged which are not what we would predict based on previous studies of how individuals sleep?
Carter - Essentially, what we found is that animals in the wild can't afford to make up for lost sleep all of the time. The ecological and social pressures seem to be really the pressures that are driving their sleep patterns. When they sleep in a new and unfamiliar environment, they sleep quite a bit less and they sleep more in a more fragmented way. They also sleep quite a bit less when they are sleeping in proximity of more group members. But, surprisingly, how much they've slept in the recent history and how much physical activity they had on the preceding day had relatively minor influence.
Chris - Presumably there's some kind of cost attached to this loss of sleep?
Carter - Presumably, yes, but we don't have a lot of data on how exactly those costs manifest. The studies that have looked at this also found difficulties in finding the exact cost of lost sleep, which brings us back to one of the central questions of sleep research which is, "Why do we sleep if we can give a up sleep without major costs?" That's something that we still just don't really have a great answer to.
Chris - You don't think it's possible that, in your animals where they have been robbed of sleep, that in fact they are cat napping here and there? I know you studied baboons not cats, but you know what I'm saying. Perhaps there is a bit of catch up going on but, actually, it's below the resolution of your ability to catch it with the accelerometer. So, they're just dropping off periodically here and there throughout the day to compensate and you're missing it.
Carter - That might be possible. But one of the beauties of accelerometry data is that we can collect continuous and really high resolution data for relatively long periods of time. So, I would say that's rather unlikely. It could be that the physiological need for sleep is playing out at time scales that we're just not looking at. So maybe they've given up sleep for 10 days or something, and then they're catching up on it in the 10 days.
22:09 - Covid antibodies to vaccine and infection
Covid antibodies to vaccine and infection
Meghan Garrett, Fred Hutchinson
The Covid-19 pandemic is now into its 3rd year, as if I needed to remind anyone! But that timeline means we're in a position to look longitudinally at the pandemic and how the virus is changing as well as how our response to it is also evolving. And when she was at the Fred Hutchinson in Seattle, Meghan Garrett was interested in the sorts of antibody responses people made, both following natural infection but also vaccination...
Meghan - This was in the first days of people getting vaccinated against SARS CoV 2. We wanted to know, is the immune response that people make against the vaccine similar to the immune response that people make against the virus itself. Can the virus escape your vaccine elicited antibodies in the same way that it can escape infection elicited antibodies?
Chris - Did you suspect there might be a difference?
Meghan - Yes. We suspected there could be a difference mainly because people get infected and they don't just get exposed to the molecules on the surface of the virus. There's a whole host of things that come with getting an infection whereas, when you just get vaccinated, you're just given in this case MRNA to make the protein by itself, alone.
Chris - So how did you pursue it, then?
Meghan - My original graduate project had been working with HIV. In that context, we built a library of phage that display all sorts of little bits of the HIV proteins in this case. Then, we can use that library and mix it together with antibodies and you see where they bind. Right as I was publishing that paper with HIV, the pandemic hit. We thought, "Let's build the library. Instead of against HIV, let's build it against SARS CoV 2." And so, this is a library that contains all of the little bits and pieces of the spike protein, but not only that, it also contains all the little bits and pieces plus one mutation. This is a library of all the possible single mutations for the spike protein on SARS CoV 2.
Chris - You can therefore ask, "Right, when a person makes a response to the vaccine versus a person who's been exposed to the disease for real, what bits of the virus are there respective responses recognising?"
Meghan - Exactly. Then, our library also allows us to dive a little deeper and look at, "Okay, so this is where the antibodies bind, but what mutations, what single mutations, could cause a loss of binding?" And that pinpoints, "What are the potential sites of escape?"
Chris - Obviously that tells us something about where variants - those that can escape from the present generation of vaccines - the direction of travel in which they may head.
Meghan - Exactly. It shows the weak spots in our immune system and where the virus could potentially take advantage and mutate and escape.
Chris - Although, of course, there are going to be some changes which the virus would never be able to make because were it to make them it would cease to operate the way SARS CoV 2 does.
Meghan - Yes, exactly. The one thing about our library is that it displays every single mutation possible, but it doesn't discriminate between mutations that are feasible, the mutations that could potentially exist on the virus, and mutations that could never exist because a mutation at that spot would just cause the protein to completely fall apart or not function. It pinpoints potential escape mutations, but it's also important to do follow up studies and see, "Okay, this mutation could cause escape, but can the virus ever actually make this mutation?" That's the next step.
Chris - What actually emerges when you compare the response that people who have been vaccinated with the present generation of vaccines versus people who have been infected with the present generation of variants we've seen that you were testing here? What emerges?
Meghan - We saw some really interesting differences and something unexpected. When we looked at vaccinated people - and we also happened to have a few samples from people that were severely infected, people that were hospitalised, and we also had samples from people that had mild infection - what was interesting to us is that the binding patterns across spike between vaccinated people and severely infected people looked super similar. If you look at people with mild infection, they have a completely different binding pattern. So, for some reason, people that are vaccinated and people that have severe infection are making antibodies that bind to the same regions, which was really interesting to us.
Chris - And is that why people who are vaccinated, we are seeing as a general trend, might still get infected, but 90% of the time they don't get severe disease.
Meghan - I don't know if that's directly why. Our hypothesis is that when you get severely infected, and when you get vaccinated, you get exposed to a ton of antigen; you're just flooded with it. When your body makes antibodies, it's given a lot more antigen, and so it will make antibodies against different regions than it would if it was just given a little bit of antigen. That's just our hypothesis because that's the similarity between people that had severe infection and that were vaccinated: they're just given a ton of antigen.
Chris - One of the things that researchers are beginning to talk about more is COVID vaccine 2.0, as they're dubbing it. The idea that we could come up with some kind of pan-coronavirus vaccine by finding the parts of the outer coat which do appear to be invariant across the strains and variants that emerge. What do you think the prospects of that are, and did you find any areas that would perhaps be good contenders to try and reinforce an immune response against those particular areas?
Meghan - Eventually, if we're not doing it now, we're probably going to be moving towards creating a vaccine against more conserved regions. This is what's happened with flu where people are trying to target the stock region, which is a lot more conserved. And it's very similar to the S2 region on spike, which is also very conserved. It has a lot of the same functions. It's taken years for the flu field to move towards, “”e should be vaccinating against these conserved regions.” And I think we've realised that earlier with SARS CoV 2, we kind of needed these vaccines quickly, and they worked great, but we're now thinking more about, “Let's do this in a more considered way.” And I think that'll be the next generation of vaccines.
29:06 - Earliest Armoured Dinosaur Discovered
Earliest Armoured Dinosaur Discovered
Shundong Bi, Indiana University of Pennsylvania
As a child, we remember standing transfixed in the London Natural History Museum in front a the remains of a massive armoured dinosaur; this was one of the group of animals that were covered in thick defensive plates, turning them into living tanks. Now a discovery in China brings us a bit closer to the root of how those animals originated and disseminated worldwide. Shundong Bi set out originally to look for ancient mammal remains but a chance meeting in a village sent him off in a very different direction, and led to the recovery of the new species Yuxisaurus kopchicki, as he explains to Chris Smith...
Shundong - You can imagine this is like an armadillo, but it's much, much bigger in size; about 3 metres long. It's a cover with the thermal plate over the body.
Chris - Basically it's a small car. Is that a reasonable comparison? That sounds long.
Shundong - It's like I say; a truck.
Chris - And when would this have been around?
Shundong - This group included stegosaurus and angolasaurus. It's a runner, from early Jurassic to late Cretaceous. It's roughly 100 million years to 70 million years ago.
Chris - Would it have weighed as much as a truck? If you'd put one of these things on the scales, what would its weight have been?
Shundong - Probably one tonne!
Chris - So it is sort of "car mass" as well. What did they eat? Do we know much about their diet?
Shundong - Based on the teeth, it probably is a herbivore. Leaves or plants, and some juicy fruit.
Chris - It's basically an elephant in terms of size for comparison. It's gonna eat like an elephant as well, and weigh as much as a car. I mean, it's a pretty big thing. How did you find this?
Shundong - I'm a mammal specialist. I was looking for the first mammal, because we believe the first mammal was found in Southwestern China, in the Yunnan province. I led the team to a site 100 kilometres west to the capital city of Yunnan Province. I went to the site and the local people showed me the dinosaur plate and I was impressed. We went out to the field, from site we would take out more than 100 bones, including skull, lower jaw, and the vertebrae.
Chris - Are you saying that the locals had already found this, or at least they'd found some specimens that were one of these, and so that gave you the clue that there were these specimens in the area?
Shundong - Yes. The area also is very rich in fossils. Before they also found a lot of species - sauropods, dinosaurs and also some theropods.
Chris - And did you get the dating from the stratigraphy, in other words, the rocks in which it's found? Or did you date it by finding out what you had got and then comparing it to other things to work out where it must sit in the timeline?
Shundong - The datings are mainly based on the rock sequence. We make a lateral comparison with the nearby locality. At that locality, they already did dating using geochemicals and also based on stratigraphy. We can say with confidence, say this early Jurassic.
Chris - Just so we can appreciate where does that sit then in the timeline of these sorts of dinosaurs, is that really early then in their evolution?
Shundong - I would say it's really early, like the beginning of the Jurassic; really early.
Chris - And so this is the sort of ancestor that would've become the big beasts, like stegosaurs and so on, that we are very familiar with playing with toys of them when we are little. Is that what you're saying? That this is probably the ancestor of some of those very big herbivorous dinosaurs that were plated and well defended.
Shundong - Yes. The other dinosaurs included most famous groups of stegosaurus, ankylosaurus. As you're familiar, stegosaurus have plates along their back. Ankylosaurus has plates all over the body. For this new species, it's a primitive member before the stegosaurus and the ankylosaurus split. It's an ancestor of stegosaurus and ankylosaurus.
Chris - Obviously, if they've got that level of defence, they must have it for a reason. There must have been, around at the same time, things capable of penetrating that sort of armor to want to attack them and eat them. Have we got some insights into what was eating these animals?
Shundong - We are uncertain at what species ate this group, because you look at these creatures, they are fully covered by their plates. I don't think as many creatures were larger than this.
Chris - And has anyone found anything like this anywhere else? You've got this from this particular part of Asia, but have you got anything like this anywhere else?
Shundong - Similar species have been found in Britain and in Germany. We are unsure which continent this group originated from, but what we can tell, based on the new discovery, we can tell that in early Jurassic, this group already spread very rapidly around the world.
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